DE19914474A1 - New peptide aldehyde and boronic acid derivatives are proteinase inhibitors useful for treatment of viral infections, especially hepatitis - Google Patents

Abstract

Peptide aldehydes and boronic acid derivatives (I) and their base salts are new. They are prepared from new peptide acetals (II) and peptide-substituted dioxaborolanes (III). Peptide aldehydes and boronic acid derivatives (I) and their base salts are new: E = CHO or B(OH)2; R<1> = 1-7C alkyl (optionally substituted with halo, CN, 1-7C alkylthio, aryl-1-7C alkylthio, aryl or heteroaryl); 2-7C alkenyl; or 2-7C alkynyl; R<2> = R2a or R2b; R2a = 1-7C alkyl (optionally substituted with OH, COOH, aryl, CONH2 or 3-7C cycloalkyl); R2b = aryl-1-7C alkoxy-1-7C alkyl or heteroaryl-1-7C alkyl; R<3> = H or 1-7C alkyl; or R<2>+R<3> = di- or trimethylene optionally substituted with OH; R<4> = 1-7C alkyl (optionally substituted with OH, 3-7C cycloalkyl, COOH, aryl, 1-7C alkylthio, cyano-1-7C alkylthio or aryl-1-7C alkylthio); 2-7C alkenyl; aryl; or 3-7C cycloalkyl; R<5> = R5a or R5b; R5a = 1-7C alkyl (optionally substituted with OH, 1-7C alkylthio, aryl, aryl-1-7C alkylthio or cyano-1-7C alkylthio); or 3-7C cycloalkyl; R5b = 3-7C cycloalkyl-1-7C alkyl; R<6> = H or 1-7C alkyl; R<7> = R7a or R7b; R7a = 1-7C alkyl (optionally substituted with OH, COOH, aryl or 3-7C cycloalkyl); or 3-7C cycloalkyl; R7b = 1-7C alkyl (which is substituted with aryl-1-7C alkylthio, aryl-1-7C alkoxy-aryl, aryl-1-7C alkoxycarbonyl, aryl-1-7C alkylcarbonyl, nitroguanidino, arylsulfonylguanidino, 1-7C alkylsulfonyl or acetamidomethylthio or heteroaryl); or is aryl; R<8> = R8a or R8b; R8a = 1-7C alkyl (which is substituted with OH, COOH or aryl); R8b = 1-7C alkyl which is substituted with SH, 1-7C alkylsulfonyl, aryl-1-7C alkoxy or aryl-heteroaryl; R<9> = R9a or R9b; R9a = 1-7C alkylcarbonyl; COOH-1-7C alkylcarbonyl; arylcarbonyl; 1-7C alkylsulfonyl; arylsulfonyl; 1-7C alkoxycarbonyl; or aryl-1-7C alkoxycarbonyl; R9b = 1-7C alkylcarbonyl (which is substituted with aryl, heteroaryl, arylaminocarbonyl, heteroarylthio, heteroarylcarbonyl, 1-7C alkoxy, arylcarbonyl, 1-7C alkoxy-1-7C alkoxy-1-7C alkoxy, arylcarbonylamino, 3-7C cycloalkyl, 1-7C alkylcarbonyl-3-7C cycloalkyl, 1-7C alkylcarbonylamino, 1-7C alkylcarbonyloxy, 1-7C alkoxycarbonyl or aryloxy); or is heteroarylcarbonyl; hydroxyfluorenylcarbonyl; heterocyclylcarbonyl; 2-7C alkynylcarbonyl; or 3-7C cycloalkylcarbonyl; provided that R<2>, R<5>, R<7>, R<8> and R<9> are not simultaneously R2a, R5a, R7a, R8a and R9a. Independent claims are also included for: (a) the preparation of the compounds (I); (b) peptide acetals of formula (II); and (c) peptide-substituted dioxaborolanes of formula (III). R<10> and R<11> = 1-7C alkyl; Q = group of formula (a) or (b): R<12> - R<17> = H or 1-7C alkyl; any COOH, OH and/or CONH2 groups present in (II) and (III) are protected.

Description

The invention relates to amino acid derivatives and a method for their manufacture. The invention also relates to pharmazeu table preparations containing these derivatives, and Ver Use of these derivatives as drugs, especially anti viral drugs.

The amino acid derivatives provided by the present invention are compounds of the general formula

wherein
E represents -CHO or -B (OH) ₂ ;
R ^{1 represents} a lower alkyl, halogeno lower alkyl, cyano lower alkyl, lower alkylthio lower alkyl, aryl lower alkylthio lower alkyl, aryl lower alkyl, heteroaryl, lower alkyl, lower alkenyl or lower alkynyl radical;
R ^{2 represents} R ^2a or R ^2b ;
R ^{2a represents} a lower alkyl, hydroxy lower alkyl, carboxy lower rigalkyl, aryl lower alkyl, aminocarbonyl lower alkyl or lower cycloalkyl lower alkyl radical;
R ^{2b represents} an aryl-lower alkoxy-aryl-lower alkyl or hetero aryl-lower alkyl radical;
R ^{3 represents} hydrogen or a lower alkyl radical or
R ² and R ³ together represent a di- or trimethylene radical which is optionally substituted by hydroxy radicals;
R ^{4 is} a lower alkyl, hydroxy lower alkyl, lower cycloalkyl lower alkyl, carboxy lower alkyl, aryl lower rigalkyl, lower alkylthio lower alkyl, cyano lower alkylthio lower alkyl, aryl lower alkylthio lower alkyl, lower alkenyl, aryl, or Lower cycloalkyl means;
R ^{5 represents} R ^5a or R ^5b ;
R ^{5a represents} a lower alkyl, hydroxy lower alkyl, lower alkyl thio lower alkyl, aryl lower alkyl, aryl lower alkylthio lower alkyl, cyano lower alkylthio lower alkyl or lower cycloalkyl radical;
R ^{5b represents} a lower cycloalkyl lower alkyl radical;
R ^{6 represents} hydrogen or a lower alkyl radical;
R ^{7 represents} R ^7a or R ^7b ;
R ^{7a represents} a lower alkyl, hydroxy lower alkyl, carboxy lower rigalkyl, aryl lower alkyl, lower cycloalkyl lower rigalkyl or lower cycloalkyl radical;
R ^{7b is} an aryl-lower alkylthio-lower alkyl, aryl-lower rigalkoxy-aryl-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, aryl-lower alkylcarbonyl-lower alkyl, nitroguanidino-lower alkyl, arylsulfonylguanide dino-lower alkylonyl, lower alkyl -, Acetamidomethylthio-lower alkyl, aryl or hetero ryl-lower alkyl means;
R ^{8 represents} R ^8a or R ^8b ;
R ^{8a represents} a lower alkyl, hydroxy lower alkyl, carboxy lower rigalkyl or aryl lower alkyl radical;
R ^{8b represents} a mercapto lower alkyl, lower alkylsulfonyl lower rigalkyl, aryl lower alkoxy lower alkyl or aryl heteroaryl lower alkyl radical;
R ^{9 represents} R ^9a or R ^9b ;
R ^9a denotes a lower alkylcarbonyl, carboxy lower alkylcarbonyl, arylcarbonyl, lower alkylsulfonyl, arylsulfonyl, lower alkoxycarbonyl, or aryl lower alkoxy carbonyl radical and
R ^{9b is} an aryl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl, arylaminocarbonyl-lower alkylcarbonyl, heteroarylthio-lower alkylcarbonyl, heteroarylcarbonyl, hydroxyfluorenylcarbonyl, heteroarylcarbonyl, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl -Lower alkoxy-lower alkylcarbonyl-, arylcarbonylamino-lower alkylcarbonyl-, lower cycloal kyl-lower alkylcarbonyl-, lower alkylcarbonyl-lower cycloalkyl-lower alkylcarbonyl-, lower alkylcarbonyl amino-lower alkylcarbonyl, heterocyclylcarbonyl-, lower alkylcarbonyloxy-lower alkylcarbonyl- lower alkylcarbonyl- lower alkylcarbonyl- Means lower alkynylcarbonyl or lower cycloalkylcarbonyl;
with the proviso that R ² , R ⁵ , R ⁷ , R ⁸ and R ⁹ do not mean R ^2a , R ^5a , R ^7a , R ^8a or R ^9a at the same time;
and salts of acidic compounds of the formula I with bases.

The compounds of formula I inhibit viral urine proteinases jump and can be used to treat viral infections be used, especially viral infections caused by Hepati tis C, hepatitis G and human GB viruses are caused.

The term "lower alkyl group" as used herein means a straight chain or branched chain alkyl group with 1 to 7, preferably 1 to 4 carbon atoms, e.g. B. one Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,  sec-butyl, tert-butyl, n-pentyl, neopentyl and the like. The term "lower alkenyl group" means a straight chain or branched chain alkenyl group with 2 to 7 carbon atoms, e.g. B. a vinyl, n-propenyl, n-butenyl and The like. The term "alkynyl radical" means a straight chain ge or branched chain alkynyl group with 2 to 7 carbons atoms of matter, e.g. B. a propargyl, 5-hexinyl, 6-heptinyl rest and the like. The term "cycloalkyl" means a cy cloalkyl group of 3 to 7 carbon atoms, d. H. a cy clopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo heptyl residue. The term "lower alkoxy group" denotes one Lower alkyl group, as previously defined, via an acid atom is bound, z. B. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy rest and the like. The term "aryl residue" denotes a monocy clic or polycyclic aromatic group, e.g. B. one Phenyl, naphthyl or the like. Which is unsubstituted or with is substituted by one or more substituents, e.g. B. are selected from lower alkyl, lower alkoxy, halo gen-, d. H. Fluorine, chlorine, bromine or iodine, halogen-lower alkyl, e.g. B. trifluoromethyl, hydroxy, sulfamoyl and acetamidors most. The term "heteroaryl residue" means a 5- or 6-membered aromatic heterocyclic group containing N, O and / or S contains as heteroatom (s) and optionally benz condensed and / or possibly in the same way as the previously defined aryl group. Furyl, Thienyl, pyridiyl, pyrimidinyl, benzofuranyl, benzothie nyl, quinolyl, isoquinolyl, indolyl and the like Examples of heteroaryl groups. The expression "heterocyclyl rest "means a saturated or partially unsaturated 5- or 6-membered heterocyclic group containing N, O and / or S. contains as heteroatom (s) and the optionally benzkonden is based and / or possibly in the same way as that Aryl group defined above is substituted and / or with oxo and / or thioxo is substituted. Examples of heterocyclyl groups are thiazolidinyl, 1,2,3,4-tetrahydropyrimidinyl,  Hexahydropyrimidinyl, 5,6-dihydropyranyl groups and the like it is understood that the previously mentioned definitions refer to the apply to respective groups if they stand alone or are combined with other groups.

The following subgroups of compounds of the formula I are preferred:

wherein E, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ^5a , R ⁶ , R ^7a , R ^7b , R ^8a , R ⁸ b, R ^9a and R ^{9b have} the meaning given above.

In the formulas I and IA to IF, R ¹ preferably denotes a lower alkyl or halogeno lower alkyl radical, in particular a fluorine lower alkyl radical. R ^2a preferably denotes a lower alkyl radical. R ³ preferably denotes hydrogen. R ⁴ preferably denotes a lower alkyl radical. R ^5a preferably denotes an aryl-lower alkyl radical. R ⁶ preferably denotes hydrogen. R ^7a preferably denotes a lower alkyl, carboxy lower alkyl, aryl lower alkyl, lower cycloalkyl lower alkyl or lower cycloalkyl radical. R ^7b preferably denotes a nitroguanidino lower alkyl, acetamidomethylthione lower alkyl or lower alkyl sulfonyl lower alkyl radical. Preferred meanings for R ^8a are carboxy-lower alkyl, hydroxy-lower alkyl or aryl-lower alkyl radicals. R ^8b preferably denotes an aryl heteroaryl lower alkyl radical. R ^9a preferably denotes a lower alkylcarbonyl, carboxy-lower alkylcarbonyl or arylcarbonyl radical. R ^9b preferably denotes a hetero arylcarbonyl, hydroxyfluorenylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl or aryl-lower alkylcarbonyl radical.

Examples of preferred compounds that fall under the formulas IA to IF fall:

Formula IA

2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -O-benzyl-L-tyrosyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -O- (2,6-dichlorobenzyl) -L-tyrosyl] amino] -4,4,4-trifluorobutyr aldehyde and
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -2- (3-thienyl) -L-alanyl] amino] -4,4,4-trifluorobutyraldehyde.

Formula IB

2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-L-α-glutamyl] -2-methyl-L -phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -N6-nitro-L-arginyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] - L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -S- (acetamidomethyl) -L-cysteinyl] -2-methyl-L -phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -S-benzyl-L-cysteinyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -3- (3-thenyl) -D-alanyl) -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -D-tryptophyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-D-tyrosyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] - L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -S- (4-methoxybenzyl) -D-cysteinyl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-D-threonyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (4-chloro-3-sulfamoylbenzoyl) -L-seryl)] - Q-benzyl-D-seryl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] - L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (4-Acetamidobenzoyl) -L-seryl)] - O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-Hydroxy-4,5-dimethoxybenzoyl) -L-seryl)] - O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (N-(2-ethylbutyryl) -L-seryl)] - O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
1 (RS) - [[N- [N- [N- [N- (N-acetyl-L-α-aspartyl) -S, S-dioxo-L-methionyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid and
1 (RS) - [[N- [N- [N- [N- [N- (N-acetyl-L-α-aspartyl) -S - [(acetamido) methyl] -L-cysteinyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid.

Formula IC

1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-L-α-glutamyl] - 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N2- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-N6- (p-toluenesulfonyl) -L-arginyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-D-tyrosyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -4-nitro-D-phenylalanyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -D-2-phenylglycyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N2- [N-acetyl-O-benzyl-L-seryl] nitro-L-arginyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-O-benzyl-L-seryl] -S-benzyl-L-cysteinyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N- [N-acetyl-O-benzyl-L-seryl] -D-tryptophyl] - 2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N2- (N-acetyl-S, S-dioxo-L-methionyl] -N6-nitro-L-arginyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] - L-leucyl] amino] propylboronic acid and
2 (RS) - [[N- [N- [N- [N2- (N-acetyl-L-tyrosyl) -N6-nitro-L-arginyl] - 2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde.

Formula ID

2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -S, S-dioxo-L-methionyl] -D-valyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -S, S-dioxo-S-methyl-L-cysteinyl] -D-valyl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -1- (2,4-dinitrophenyl) -L-histidyl] -D-valyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-cysteinyl] -D-valyl] -2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde and
1 (RS) - [[N- [N- [N- [N- [N-acetyl-l- (2,4-dinitrophenyl) -L-histidyl] -L-2-cyclohexylglycyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid.

Formula IE

2 (RS) - [[N- [N- [N- [N- [N- [4- (4-methylphenyl) butyryl] -L-α-aspartyl] -L-cL-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [3- (4-methylbenzoyl) propionyl] -L-α-aspartyl] -L-cx-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- [2- (2- (2-methoxyethoxy) ethoxyacetyl] -L- α-aspartyl] -L-α-glutamyl] -2 -methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- (4-oxo-2-thioxo-3-thiazolidinyl) acetyl] -L-α-aspartyl] -IJ-α -glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [3- (2-methyl-4-nitro-1-imidazolyl) per pionyl] -L-α-aspartyl] -L- α-glut amyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (5-hexinoyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(6-quinolyl) carbonyl] -L-α-aspartyl] - L-α-glutamyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(6-oxo-3-pyranyl) carbonyl] -L-α-aspartyl] -L-α-glutamyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- (1,3-Benzodioxol-5-yl) acetyl] -L-α-aspartyl] -L-α-glutamyl ] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(5,6-dihydro-6,6-dimethyl-4-oxo-4H-pyran-2-yl) carbonyl] - L-α-aspartyl] -L-cx-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-tri fluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- (2-naphthyl) acetyl] -L-α-aspartyl] - L-α-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [N- (3-Benzamidopropionyl) -L-α-aspartyl] - L-α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinyl) carbonyl] -L-α- aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-methyl-2-thenoyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L -phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (N-(2-Cyclohexylacetyl) -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2 (RS) - (4-nitrophenyl) propionyl] -L-α-aspartyl] -L-α-glutamyl] -2 -methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
1 (RS) - [[N- [N- [N- [N- [N - [(6-oxo-6H-pyran-3-yl) carbonyl] -L-α-aspartyl] -L-α-glutamyl ] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N- [N- (4-acetamidobutyryl) -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl) -L-leucyl] amino] propylboronic acid and
1 (RS) - [[N- [N- [N- [N - [- N- (2-acetoxyacetyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid.

Formula IF

2 (RS) - [[N- [N- [N- [N- [N- [2- (2,4,6-trimethylphenyl) acetyl] -L-seryl] -O-benzyl-D-seryl] - 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(IH-Benzotriazol-5-yl) carbonyl-L-seryl] -O-benzyl-D-seryl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [4- (phenylcarbamoyl) butyryl] -L-seryl] - O-benzyl-D-seryl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] - L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2 - [(4,6-dimethyl-2-pyrimidinyl) thio] acetyl] -L-seryl] -O-benzyl- D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] aminoj-4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(2-chloro-3-pyridyl) carbonyl] -L-seryl] - O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] - L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(9-hydroxy-9-fluorenyl) carbonyl-L-seryl] -O-benzyl-D-seryl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(2-furoyl) -L-seryl] -O-benzyl-D-seryl] - 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2 (RS) - (4-nitrophenyl) propionyl] -L-seryl] -O-benzyl-D-seryl] -2 -methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- (2-chlorophenyl) acetyl) -L-seryl] -O-benzyl-D-seryl) -2-methyl- L-phenylalanyl) -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [N- (2-ethoxyacetyl) -L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde and
2 (RS) - [[N- [N- [N- [N- [N - [(3-fluoro-4-hydroxyphenyl) acetyl] -L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde.

According to the method provided by the invention, the compounds of formula I and the salts of the acidic compounds of formula I with bases are prepared by

• a) for the preparation of a compound of formula I, wherein E is CHO, by an acetal of the general formula
  wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 have} the meaning given above, with the proviso that each car boxy, hydroxy and / or aminocarbonyl group , which is present, is in protected form, and R ¹⁰ and R ¹¹ each represent lower alkyl radicals, is deacetalized and, if necessary, the protective groups are split off or
• b) for the preparation of a compound of formula I, in which EB (OH) is ₂ , in a substituted dioxaborolane of the general formula
  wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 have} the meaning given above, with the proviso that each car boxy, hydroxy and / or aminocarbonyl group which is present, is in protected form, and Q is a group of the formula
  means, wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ each mean What hydrogen or lower alkyl radicals mean, the ring is opened and, if necessary, protecting groups are split off and
• c) if desired, an acidic compound of formula I with a base is converted into a salt.

Protected carboxy, hydroxy and aminocarbonyl groups which are present in the acetal starting material of the formula II and which may be present in the substituted dioxaborolane starting material of the formula III are carboxy, hydroxyl or aminocarbonyl groups which are protected with a conventional protective group, which is known from peptide chemistry. In particular, R ² , R ⁴ , R ⁷ , R ⁸ and / or R ^{9 can} preferably mean tert-butoxycarbonyl-lower alkyl radicals as protected carboxy radicals, R ² , R ⁴ , R ⁵ , R ⁷ , R ⁸ and / or R ⁹ can preferably be lower alkyl-O-tert-butyl ether as protected hydroxyl groups and R ² can preferably be a tritylaminocarbonyl lower alkyl group as protected aminocarbonyl lower alkyl group.

The deacetalization of an acetal of the formula II, preferably one in which R ¹⁰ and R ^{11 are} each methyl radicals, according to embodiment a) of the process according to the invention can be carried out in a manner known per se. It is usually effected using trifluoroacetic acid or an equivalent strong acid in the presence of an inert organic solvent such as a halogenated aliphatic hydrocarbon, e.g. B. dichloromethane, and in the presence of water. The deacetalization is suitably carried out at about room temperature. If protected carboxy, hydroxy and / or aminocarbonyl groups are present in the acetal starting material, these are converted to free carboxy, hydroxy and / or aminocarbonyl groups under the conditions of deacetalization.

According to a variant of embodiment a) of the invention According to the process, an acetal starting material of the formula II bound to a solid phase peptide synthetic resin. In this The split from the resin occurs among those for the De conditions used instead of acetalization.

The ring opening of a substituted dioxaborolane of the formula III, in which Q is a group of the formula (a), preferably one in which R ¹² , R ¹³ , R ¹⁴ and R ^{15 are} each methyl radicals, in accordance with embodiment b) of the process according to the invention can also be carried out in a manner known per se. Usually the ring opening is carried out using trifluoroacetic acid or an equivalent strong acid in an inert organic solvent, e.g. B. a halogenated aliphatic hydrocarbon, such as dichloromethane, and optionally in the presence of water. The ring opening is suitably carried out at about room temperature. If protected carboxy, hydroxy and / or aminocarbonyl groups are present in the substituted dioxaborolane starting material, these are converted to free carboxy, hydroxy and / or aminocarbonyl groups under the conditions of ring opening.

The ring opening of a substituted dioxaborolane of the formula III, in which Q is a group of the formula (b), in particular if one of the radicals R ¹⁶ and R ^{17 is} hydrogen and the other is a methyl group in accordance with embodiment b) of the process according to the invention, can be carried out in the usual way. Usually the ring opening is carried out using a periodate, in particular an alkali periodate, e.g. B. sodium periodate in a buffered aqueous organic medium, suitably at about room temperature. Advantageously, the medium consists of a mixture of an inert water-miscible organic solvent, e.g. B. acetone, and aqueous ammonium acid. Each protected carboxy, hydroxy and / or aminocar bonyl group, which is present in the substituted dioxaborolane starting material, is cleaved in a manner known per se, e.g. B. by treating with trifluoroacetic acid before the ring opening.

According to a variant of embodiment b) of the process according to the invention, a substituted dioxaborolane of the formula III, in which Q denotes a group of the formula (a), is bound to a solid-phase synthesis resin. The binding typically takes place via an alkyl group R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ , which is bound to the resin via an amide bridge. Cleavage from the resin takes place under the conditions used for mode b) of the process.

According to embodiment c) of the process, acidic ver compounds of the formula I are converted into salts with bases, e.g. B. with alkali salts, such as sodium or potassium salts, Erdal potash salts, such as calcium or magnesium salts, salts with or  ganic bases, e.g. B. salts with amines, such as N-ethyl pipe ridin, procaine or dibenzylamine, or salts with basic Amino acids, such as salts with arginine or lysine. The education and isolation of such salts can be carried out using known Me methods are carried out.

The acetal starting materials of the formula II are new and also form the subject of the present invention. You can e.g. B. be prepared by first a hydroxamate of the general formula

wherein R ¹ , R ¹⁰ and R ^{11 have} the meanings given above, and Q ^{1 is} an amino protecting group, for. B. means a tert-butoxy carbonyl group, with an alkali aluminum hydride, for. B. lithium aluminum hydride, the product is treated with methanolic hydrochloric acid to the hydrochloride salt of a compound of general formula

wherein R ¹ , R ¹⁰ and R ^{11 have} the meaning given above, and then either this is subjected to a successive coupling with the respective amino acids or a fragment obtained during such a sequential coupling is subjected to a further coupling with a peptide derivative of suitable length becomes. Alternatively, a compound of formula V can be coupled with a suitable pentapeptide.

The previously mentioned coupling reactions can be found in the Peptide chemistry can be carried out in a manner known per se Licher using the respective amino acid or the suitably protected di, tri, tetra or Pentapeptide as described above and also by adding each ami nogroup which is present with Fmoc [(9-fluorenyl) methoxy carbonyl] in the presence of hydroxybenzotriazole, 1- (3-dime thylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-methyl morpholine in an inert organic solvent, e.g. B. a halogenated hydrocarbon such as dichloromethane protects.

The hydroxamates of the formula IV, which are used to prepare the Ace valley starting material of the formula II are required known compounds or analogs of known compounds gene, the herge in an analogous manner to known compounds can be put.

The acetal starting material of the formula II can also be obtained from a Compound of formula V on a solid phase peptide synthesis resin are synthesized. This method is known and is detailed in the Handbook from Fourth International Symposi um on Solid Phase Synthesis and Combinatorial Chemical Libra Ries, Edinburgh, 1995.

The substituted dioxaborolanes of the formula III, which are used as starting materials for embodiment b) of the process according to the invention, are new and form a further object of the present invention. You can e.g. B. can be prepared as explained in the following Scheme A, wherein R ¹ and Q have the meaning given above:

Scheme A

With regard to Scheme A, a compound of Formula VI with an alkali bis [tri (lower alkyl) silyl] amide, e.g. B. lithium bis (trimethylsilyl) amide, in an inert organi rule solvents such as ether, e.g. B. diethyl ether or Te trahydrofuran, reacted and then with a strong acid, e.g. B. trifluoroacetic acid, which is a compound of Formula VII gives.

In step b) a compound of formula VII is converted into a ver bond of formula III converted, either by coupling with a pentapeptide, by sequential coupling with the respective amino acids or by coupling one during the sequential coupling obtained fragment s with a peptide derivative of the desired length, the amino acid or Peptide that are used are appropriately protected as described above, and also any existing amino group is protected with Fmoc. These coupling reactions can in a manner known per se, such as in peptide chemistry known to be performed, e.g. B. using the Ami nonic acid or the peptide in the form of a mixed anhydride, that with a lower alkyl halide form such as isobutyl chlorine formate, is formed and by the coupling in the presence a suitable base, e.g. B. a tertiary organic base, such as N-methylmorpholine.  

Substituted dioxaborolanes of the formula III, which were obtained in the preceding coupling and which carry a protective group on the substituent of R ² , R ⁴ , R ⁵ , R ⁷ , R ⁸ and / or R ⁹ , can be selectively in a conventional manner be freed from the protecting groups, e.g. Example, using trifluoroacetic acid, and converted into the corresponding compounds which carry a free carboxy, hydroxy and / or aminocarbonyl group on the respective substituent, while the protected boronic acid fraction denoted by Q is retained. These selectively deprotected compounds are also active as inhibitors of proteinases of viral origin and can be used for the treatment of viral infections in the same way as the compounds of the formula I.

Compounds of formula VI can, for. B. be prepared from a compound of the general formula

Cl ₂ CH-Q (VIII)

wherein Q has the meaning given above, which is a known compound or is an analog of a known compound, by reaction with a compound of the formula R ¹ -MgHal, wherein R ^{1 has} the meaning given above and Hal is halogen, preferably bromine. The reaction is carried out under the usual conditions for a Grignard reaction, e.g. B. in an inert organic solvent such as an ether, e.g. B. diethyl ether or tetrahydrofuran. When Q represents a group of formula (b), the reaction is carried out in the presence of zinc chloride.

A compound of formula VI in which R ^{1 represents} a bromo-lower alkyl or fluoro-lower alkyl radical and Q represents a group of the formula (a) can, for. B. be prepared by a bromine or fluorine lower alkene, e.g. B. 3-bromopropene or 3-fluoropropene, is hydroborated, the hydroboration product with a diol of the formula R ¹² R ¹³ C (OH) -C (OH) R ¹⁴ R ¹⁵ is converted, wherein R ¹² , R ¹³ , R ¹⁴ and R ^{15 have} the meaning given above, for. B. 2,3-dimethyl-2,3-butanediol, and the resulting 2- (bromo or fluoro-lower alkyl) -1,3,2-dioxaborolane with dichloromethane in the presence of lithium diisopropylamine. The hydroboration can be carried out in a conventional manner, e.g. B. using phenylboronic acid at elevated temperature, e.g. B. about 100 ° C in the absence of a solvent or using a borane-dimethyl sulfide complex in the presence of cyclohexene in an inert organic solvent, e.g. As dimethoxyethane, at about 0 ° C, followed by treatment with trimethylamine N-oxide.

A substituted dioxaborolane of the formula III, in which Q represents a group of the formula (a), can also be synthesized on a solid phase peptide synthetic resin. For example, a 4-methylbenzhydryl resin with a dioxaborolanyl-valeric acid of the general formula

wherein R ¹ , R ² , R ¹² , R ¹⁴ , R ¹⁵ and Q ^{1 have} the meaning given above, are implemented and the product can be converted into the required resin-bound starting material by successive deprotection and coupling with a protected amino acid.

Compounds of the formula IX can be prepared in a suitable manner by adding a tert-butyl-6,7-dihydroxy-3,6,7-tri (lower alkyl) -6-octenoate with dichloromethyldiisopropoxybo ran, the resulting compound of the general formula

wherein R ¹² , R ¹⁴ and R ^{15 have} the meaning given, with a compound of the formula R ¹ MgHal, wherein R ^{1 has} the meaning given above, and Hal is halogen, preferably bromine, under the conditions of a Grignard reaction is, the resulting compound of the general formula

wherein R ¹ , R ¹² , R ¹⁴ and R ^{15 have} the meaning given above, is reacted with an alkali bis [tri (lower alkyl) silyl] amide which is the resulting compound of the general formula

wherein R ¹ , R ¹² , R ¹⁴ and R ^{15 have} the meaning given above, with a protected amino acid of the general formula

Q ² HN-CH (R ² ) -COOH (XIII)

wherein R ^{2 has} the meaning given above and Q ² Fmoc means, condenses and the resulting compound of the general formula

wherein R ¹ , R ² , R ¹² , R ¹⁴ , R ¹⁵ and Q ^{2 have} the meaning given above, saponified.

As previously mentioned, the compounds of formula I and Salts of acidic compounds of the formula I with bases Inhibi gates of proteases of viral origin. The activity against over such a protease, namely HCV protease, can be under Using the following test:

Construction of a plasmid for the expression of MBP-NS3''Gly ₁₂ - NS4A enzyme in E. coli

The nucleotide sequence of this expression plasmid is in SEQ ID No. 1, which is attached as an attachment, and the Ami The acidic sequence of the expression product is in SEQ ID No. 2, which is also attached as an annex. You ba based on the pMAL®-c2 vector, which is from New England Biolabs, Inc. (32 Tozer Rd., Beverly, MA, USA). The. Principle of construction was one in the reading frame Fusion of the maltose binding protein (MBP) gene, which  from which pMAL-c2 vector is contributed, with sequences of HCV genome, which are necessary for the NS3 proteinase Activity to generate. These HCV sequences were between the EcoRI and HindIII sites of the pMAL-c2 polylinker (positions 2695 or 3556 of the one specified in SEQ ID No. 1 sequence).

The HCV sequences were derived from plasmids pDS 3348-4045 and pBFK 3348-6062, which are described by Bartenschlager et al., 1993 (Journal of Virology, 67, 3835-3844). The regions comprising the NS3 proteinase domain (amino acids 1007-1219) and the NS4A domain (amino acids 1658-1711) were isolated and inserted into the pMAL-c2 vector using standard genetic engineering techniques, including PCR amplification of the required sequences. A linker region was constructed between the NS3 and NS4A domains using synthetic oligonucleotides (positions 3343-3390; amino acids 606-621). The resulting plasmid was used to transform E. coli (strain MC 1061) cells and the expression of the MBP-NS3''Gly ₁₂ -NS4A enzyme was induced as described below.

Protein expression and purification

E. coli (strain MC 1061) cells that match the previous Plasmid were transformed into Luria broth at 37 ° C grown containing ampicillin (100 µg / ml). The cells were grown until an optical density of 0.5 at 600 nm was reached, and enzyme expression was then induced by adding 1 mM isopropylthiogalactoside and at 37 ° C was incubated for a further 3 hours. The cells were harvested by centrifugation and stored at -80 ° C.

A 4 l pellet of a bacterial culture was in E. coli Lysis buffer (20 mM Tris-HCl, pH 7.5, the 150 mM NaCl, 1 mM EDTA and 10 mM dithiothreitol contained) and the  Cell lysis was achieved through two passages through a French Press. The clear supernatant, obtained by centrifugation (18,000 g, 30 minutes) was then applied to an amylose resin column (4 × 1 cm) (New England Biolabs) applied to the with ice-cold 50 mM Tris-HCl, pH 8.5, the 200 mM NaCl, 1 mM Contained dithiothreitol and 5% glycerol, was equilibrated. The column was carefully washed with the equilibration buffer wash and bound protein was eluted using of the equilibration buffer containing 10 mM maltose. Frak 1 ml portions were collected, with the Fractio that contained the enzyme were summarized and at -80 ° C. The enzyme concentration was below searches with the method of M.B. Bradford, Analytical Biochemi stry, 1976, volume 72, page 248.

test

Compounds of the formula I (routinely prepared as stock solution in DM50) were tested for their ability to remove a substrate with quenched fluorescence [NS4A / BF peptide (N- [4- [4- (dimethylamino) phenylazo] benzoyl] - L- α-aspartyl-L-α-glutamyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-cysteinyl-L-alanyl-L-seryl-L-histidyl-N5- [2- (5th -sulfo- 1-naphthylamino) ethyl] -L-glutaminamide); Wilkinson et al., So ciety for General Microbiology Meeting, University of Warwick, England, March 28, 1996] based on the NS4A / 4B cleavage site to inhibit the enzyme MBP-NS3''Gly ₁₂ -NS4A in microplates as follows :
The enzyme (0.4 to 0.6 μg) became a mixture (200 μl final volume) containing 50 mM Tris-HCl, pH 8.5, with 1 mM NaCl, 0.1 mM EDTA, 1 mM dithiothreitol, 0 , 1% Triton X-100, 10 µM NS4A / BF peptide and the test compound of the formula I, which had been prepared as a stock solution in DMSO, were added and enough DMSO was added that a 10% final concentration was obtained. The resulting mixture was incubated at room temperature for 60 minutes and the reaction ended by adding 100 ul 2 M sodium dihydrogen orthophosphate. The progress of the reaction was evaluated with a Millipore Cytofluor 2350 using an excitation wavelength of 360 nm and an emission wavelength of 530 nm. The reduction in fluorescence in the presence of the inhibitor was measured and plotted against the inhibitor concentration. The inhibitor concentration that caused a 50% reduction (IC ₅₀ ) was calculated by manual graph analysis.

The results obtained in the previous test with the respective some compounds of formula I are in the following Ta belle set up:

table

links

A = 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl-L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] - O-benzyl-L-tyrosyl) amino] -4,4,4-trifluorobutyraldehyde.
B = 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl- O-benzyl-L-α-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde.
C = 2 (RS) - [[N- [N- [N- [N2- (N-acetyl-L-tyrosyl) -N6-nitro-L-arginyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde.
D = 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-cysteinyl] - D-valyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde.
E = 1 (RS) - [[N- [N- [N- [N- [N- (4-acetamidobutyryl) -L-α-aspartyl-L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] - L-leucyl] amino] propylboronic acid.
F = 2 (RS) - [[N- [N- [N- [N- [N- (9-Hydroxy-9-fluorenyl) carbonyl] -L-seryl] -O-benzyl-D-seryl] -2 -methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde.

The compounds of formula I and salts of acidic compounds gene of formula I with bases can be used as a drug be, e.g. B. in the form of pharmaceutical preparations. The pharmaceutical preparations can be enteral, e.g. B. orally in the form of tablets, coated tablets, coated tablets, hard and Soft gelatin capsules, solutions, emulsions or suspensions, nasal, e.g. B. in the form of nasal sprays, or rectally, e.g. B. in Form of suppositories. However, you can too administered parenterally, e.g. B. in the form of injection solution sung.

The compounds of formula I and the aforementioned salts can with pharmaceutically inert, organic or inorganic carriers for the production of pharmaceutical preparations rates are processed. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like are used, e.g. B. coated as a carrier for tablets Tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are e.g. B. vegetable oils, waxes, Fat, semi-solid and liquid polyols and the like; depending on however, the type of active ingredient is usually in the In the case of soft gelatin capsules, no carriers are required. Ge suitable carriers for the production of solutions and syrups are z. B. water, polyols, sucrose, invert sugar, glucose and the like. Suitable suppositories are e.g. B. natural  or hardened oils, waxes, fats, semi-liquid or liquid Polyols and the like

The pharmaceutical preparations can also contain preservatives tel, solubilizers, stabilizers, wetting agents tel, enulsifiers, sweeteners, colors, flavors, salts to vary the osmotic pressure, buffer, masking agent tel or contain antioxidants. You can also do other things re contain therapeutically valuable substances.

Medicament containing a compound of formula I or a salt an acidic compound of formula I together with a base with a compatible pharmaceutical carrier also subject of the present invention, as well as a Process for the preparation of such medicaments, which comprises that one or more of these compounds or salts and, if desired, one or more others of therapeutic value brings full substances into a galenical form of administration together with a compatible pharmaceutical carrier.

As previously mentioned, the compounds of formula I and Salts of acidic compounds of formula I with bases invented appropriately as therapeutically active substances, in particular used as an antiviral. The dosage can vary within wide limits and will of course depend on the individual requirements in each special case fit. In general, in the case of administration Adults a usual daily dosage of about 3 mg to about 3 g, preferably about 10 mg to 1 g. The daily dose tion can be taken as a single dose or in the form of a distributed dose can be administered and in addition the upper dose limit previously referred to exceeded if this turns out to be indicated.

Finally, the use of compounds of the For mel I and salts of acidic compounds of formula I with Ba  sen for the production of drugs, especially anti viral drugs, subject of the invention.

example 1

0.02 g (0.006 mmol) 5- [4 - [[N- [N- [N - [(9-fluorenyl) methoxycar bonyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] - N- [3,3,3-trifluoro-1 (RS) - (dimethoxymethyl) propyl] amino] methyl] -3,5-dimethoxyphenoxy] -N- (4-methyl-α- (RS) phenyl benzyl) valeramide-polystyrene conjugate were in 0.7 ml dime thylformamide / piperidine (4: 1) suspended and stirred. After 5 The resin was dewatered for minutes and then with 0.7 ml of Dime Suspend thylformamide / piperidine (4: 1) for a further 5 minutes dated and stirred. The resin was then removed and five times washed with 1.5 ml of dimethylformamide.

The resin was then dissolved in a solution of 0.028 g (0.06 mmol) N - [(9-fluorenyl) methoxycarbonyl] -O-benzyl-α-glutamic acid in 0.3 ml of dimethylformamide suspended and then a mixture 0.019 g (0.06 mmol) of 2- (IH-benzotriazol-1-yl) -1,1,3,3- tetramethyluronium tetrafluoroborate and 0.012 g (0.12 mmol) N-methylmorpholine, dissolved in 0.3 ml of dimethylformamide, is added ben. After stirring for two hours, the resin was removed and washed five times with 1.5 ml of dimethylformamide.

The resin was again in 1.5 ml of dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin became removed and again in dimethylformamide / piperidine (4: 1) white Suspended and stirred for another 5 minutes. Then the resin removed and washed five times with 1.5 ml of dimethylformamide.

The resin was then dissolved in a solution of 0.025 g (0.06 mmol) N - [(9-fluorenyl) methoxycarbonyl] -O-tert-butyl-L-α-aspara Ginsäure suspended in 0.3 ml of dimethylformamide and then one Mixture of 0.019 g (0.06 mmol) of 2- (1H-benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate and 0.012 g (0.12  mmol) of N-methylmorpholine dissolved in 0.3 ml of dimethylformamide given. After stirring for two hours, the resin was removed and washed five times with 1.5 ml of dimethylformamide.

The resin was again in 1.5 ml of dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin became removed and again in dimethylformamide / piperidine (4: 1) white Suspended and stirred for 5 minutes. Then that became Resin removed and washed five times with 1.5 ml of dimethylformamide .

The resin was then dissolved in a solution of 0.01 g (0.06 mmol) tert-butyl hydrogen succinate in 0.3 ml of dimethylformamide sus pendulum and with a mixture of 0.019 g (0.06 mmol) 2- (1H-Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoro borate and 0.012 g (0.12 mmol) N-methylmorpholine, dissolved in 0.3 ml of dimethylformamide. After stirring for two hours the resin was removed and five times with 1.5 ml of dimethylfor mamide and then washed twice with 1.5 ml dichloromethane.

The resin was washed with 0.8 ml trifluoroacetic acid / water (19: 1) added and then stirred for 30 minutes. Then it got down filtered and ge with 0.8 ml trifluoroacetic acid / water (19: 1) to wash. The combined trifluoroacetic acid / water mixtures were then evaporated in a vacuum centrifuge, centrifuge and the residue in 0.8 ml acetonitrile / water (1: 1) suspended and freeze-dried. 6.3 mg 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl- L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L- leucyl] amino] -4,4,4-trifluorobutyraldehyde (1: 1 mixture of Diastereomers) obtained as a white solid; M5: m / e 963.4 [M + H] ⁺.

The starting material was produced as follows:

i) 18 g (60.0 mmol) of N, O-dimethyl-2 (RS) - (tert.-butoxyform amido) -4,4,4-trifluorobutyrohydroxamate were dissolved in 230 ml of water-free tetrahydrofuran and the solution was brought to 0 ° C cooled. 48 ml (48 mmol) of a 1 M solution of lithium aluminum hydride in tetrahydrofuran was then added dropwise while the temperature was kept at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes and then the batch was quenched to pH 1 by the dropwise addition of saturated potassium hydrogen sulfate solution while the temperature was kept below 20 ° C. The resulting white slurry was stirred vigorously for a further 30 minutes and then divided into 3 equal aliquots in diethyl ether. The combined diethyl ether fractions were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was then dissolved in 100 ml of anhydrous saturated methanolic hydrogen chloride solution and left at 4 ° C. overnight. The mixture was evaporated and the residue was triturated with dichloromethane. The filtrate was evaporated and the residue was chromatographed on silica gel using 5% methanol, 3% acetic acid and 1.5% water in dichloromethane for the elution. 8.80 g of 3,3,3-trifluoro-2 (RS) - (dimethoxymethyl) propylamine hydrochloride were obtained as a white solid. ¹ H-NMR: (CDCl ₃ ) δ: 2.60-2.96 (n , 2H), 3.49 (d, 6H), 3.57-3.69 (q, 1H), 4.66 (d, 1H), 8.72 (br 5, 3H).

ii) To a stirred mixture of 5.6 g (25.0 mmol) of 3,3,3-trifluoro-2 (RS) - (dimethoxymethyl) propylamine hydrochloride, 3.65 ml of triethylamine, 7.8 g (25.0 mmol ) 4- [4- (Ethoxy carbonyl) butoxy] -2,6-dimethoxybenzaldehyde and 25 g of 3 Å molecular sieves in dichloromethane were added 5.8 g (27.5 mmol) of sodium triacetoxyborohydride. After 3 hours the molecular sieves were removed by filtration. The filtrate was then washed with three equal aliquots of saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate and filtered. The solvent was removed by evaporation and the resulting orange oil was chromatographed on silica gel using 60% ethyl acetate in hexane for the elution. 10.4 g of ethyl 5- [4- [[3,3,3-trifluoro-1 (RS) - (dimethoxymethyl) propylamino] methyl] -3,5-dimethoxyphenoxy] valerate were obtained as a pale orange oil;
¹ H-NMR: (CDCl ₃ ) δ: 1.25 (t, 3H), 1.78-1.87 (m, 4H), 2.18-2.52 (m, 4H), 2.86- 2.92 (m, 1H), 3.33 (d, 6H), 3.77 (s, 6H), 3.81 (d, 2H), 3.96 (t, 2H), 4.13 (q , 2H), 4.26 (d, 1H), 6.18 (s, 2H); MS: m / e 482.2 [M + H], 504.2 [M + Na].

iii) A solution of 6.6 g (18.7 mmol) of N - [(9-fluorenyl) - methoxycarbonyl] -L-leucine and 9.7 g (18.7 mmol) 7-azabenzo triazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate in 50 ml of anhydrous dichloromethane for 15 minutes stirred at room temperature. This mixture then became 6.0 g (12.4 mmol) of ethyl 5- [4 - [[3,3,3-trifluoro-1 (RS) - (dimeth oxymethyl) propylamino] methyl] -3,5-dimethoxyphenoxy] valerate and 4.3 ml (24.8 mmol) of diisopropylethylamine were added. After Stirring overnight at 25 ° C was the mixture with dichlor diluted methane and successively with water, 10% Citro sensic acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, then washed over water free magnesium sulfate dried and filtered. The solution medium was removed by evaporation and the residue Silica gel chromatographed using 30% ethyl acetate in hexane for elution. 8.06 g of ethyl 5- [4- [[N- [N - [(9-fluorenyl) methoxycarbonyl] -L-leucyl] -N- [3,3,3- trifluoro-1 (RS) - (dimethoxymethyl) propyl] amino] methyl] -3,5- obtained dimethoxyphenoxy] valerate; MS: m / e 839.4 [M + Na], 855.3 [M + K].

iv) 8.0 g (9.8 mmol) of 5- [4 - [[N- [N - [(9-fluorenyl) methoxycarbo nyl] -L-leucyl] -N- [3,3,3-trifluoro-1 (RS) - (dimethoxymethyl) pro pyl] amino] methyl] -3,5-dimethoxyphenoxy] valerate and 40 ml Pi peridine were dissolved in 145 ml dry dichloromethane and the solution was stirred at room temperature for 30 minutes. she was then evaporated in vacuo and the residue opened Silica gel chromatographed using 2% methanol,  49% dichloromethane and 49% hexane followed by 5% methanol, 47.5% dichloromethane and 47.5% hexane for the elution. It was the 4.09 g of ethyl 5- [4 - [[N- [3,3,3-trifluoro-1 (RS) - (dimethoxyme thyl) propyl] -N- (L-leucyl) amino] methyl] -3,5-dimethoxyphenoxy] Obtain valerat as a clear, solid oil; MS: m / e 595 [M + H].

v) A solution of 2.76 g (7.8 mmol) of N - [(9-fluorenyl) - methoxycarbonyl] -3-methyl-L-valine, 1.60 g (8.5 mmol) 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1, 60 g (10.7 mmol) N-hydroxybenzotriazole in 70 ml dichloromethane was stirred at 0 ° C for 15 minutes. Then 4.06 g (7.1 mmol) ethyl 5- [4 - [[N- [3,3,3-trifluoro-1 (RS) - (dimethoxyme thyl) propyl] -N- (L-leucyl) amino] methyl] -3,5-dimethoxyphenoxy] valerate and 2.7 ml (21.3 mmol) N-ethylmorpholine in 70 ml Dichloromethane added. After stirring overnight at room temperature the mixture was consecutively heated with 10% Citro sensic acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, then washed over water free magnesium sulfate dried, filtered and evaporated. The residue was chromatographed on silica gel under Use 35% ethyl acetate in hexane for elution. It 6.11 g of ethyl 5- [4 - [[N- [N- [N - [(9-fluorenyl) methoxy carbonyl] -3-methyl-L-valyl] -L-leucyl] -N- [3,3,3-trifluoro- 1 (RS) - (dimethoxyethyl) propyl] amino] methyl] -3,5-dimethoxyphen oxy] valerate obtained as a white foam; MS: m / e 952.5 [M + Na], 968.5 [M + K].

vi) 5.8 g (6.3 mmol) of ethyl 5- [4 - [[N- [N- [N - [(9-fluorenyl) methoxycarbonyl] -3-methyl-L-valyl] -L-leucyl] -N- [3,3,3-tri fluoro-1 (RS) - (dimethoxyethyl) propyl] amino] methyl] -3,5-dimeth oxyphenoxy] valerate and 18 ml piperidine were in 90 ml Dissolved dichloromethane and the solution at room temperature 1 Stirred for an hour. It was then evaporated and the back stand chromatographed on silica gel using 3% Methanol, 48.5% dichloromethane and 48.5% hexane for the elu tion. 4.1 g of ethyl 5- [4 - [[N- [3,3,3-trifluol-1 (RS) -  (dimethoxymethyl) propyl] -N- [N- (3-methyl-L-valyl) -L-leucyl] amino] methyl] -3,5-dimethoxyphenoxy] valerate as a white foam receive; MS: m / e 708.6 [M + H], 730.5 [M + Na].

vii) 4.0 g (5.7 mmol) of ethyl 5- [4 - [[N- [3,3,3-trifluoro-1 (RS) - (dimethoxymethyl) propyl] -N- [N- (3rd -methyl-L-valyl) -L-leucyl] amino] methyl] -3,5-dimethoxyphenoxy] valerate were dissolved in 40 ml of methanol. 2.4 g (17.3 mmol) of potassium carbonate and 8.0 ml of water were then added and the mixture was stirred at room temperature for 2 days. The solvent was removed by evaporation and the residue was dissolved in 20 ml of water and 20 ml of dioxane. 2.9 g (8.6 mmol) of N - [(9-fluorenyl) methoxycarbonyloxy] succininide was then added and the mixture was stirred for 3 hours. The pH of the mixture was adjusted to 3 with 10% citric acid and then washed with 3 equal aliquots of dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using 4% tert-butyl methyl ether in dichloromethane for the elution. 5.12 g of 5- [4 - [[N- [N- [N - [(9-fluorenyl) methoxycarbonyl] -3-methyl-L-valyl] -L-leucyl] -N- [3.3 , 3-trifluoro-1 (RS) - (dimethoxymethyl) propyl] amino] methyl] -3,5-dimethoxyphenoxy] valeric acid obtained as a white foam; MS: m / e 870.8 [M + H-MeOH], 888.7 [M + H-CH ₃ ], 889.7 [M-CH ₃ ], 902.7 [M + H], 924.7 [M + Na].

viii) 5.4 g (5.4 mmol) of 4-methylbenzylhydrylamine resin were in Swollen 30 ml of dimethylformamide, excess solution poured medium from the resin and then twice with 20 ml of dime thylformamide / N-methylmorpholine (9: 1) washed. The resin was de then in 10 ml dimethylformamide containing 4.98 g (5.4 mmol) 5- [4 - [[N- [N- [N - [(9-fluorenyl) methoxycarbonyl] -3-methyl-L- valyl] -L-leucyl] -N- [3,3,3-trifluoro-1 (RS) - (dimethoxymethyl) propyl] amino] methyl] -3,5-dimethoxyphenoxy] valeric acid and 1.74 g (5.4 mmol) of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetrame  contained thyluronium tetrafluoroborate, resuspended. There were 1.18 ml (10.8 mmol) N-methylmorpholine dissolved in 10 ml dime added thylformamide. The resulting mixture became 2nd Stirred for hours and the resin was then poured off and washed five times with 30 ml of dimethylformamide. The resin was then in 30 ml of dimethylformamide, the 2.03 ml (21.6 mmol) of it acetic anhydride and 2.96 ml (27 mmol) N-methylmorpholine ent held, resuspended. This mixture was for 30 minutes stirred and then poured the resin and five times with 30 ml Washed dimethylformamide. The resin was dissolved in 30 ml of dimethyl formamide / piperidine (4: 1) resuspended and stirred. After 5 Minutes the resin was poured off again in the previous the dimethylformamide / piperidine mixture suspended and wide re stirred for 5 minutes. The resin was then poured off and washed five times with 30 ml of dimethylformamide.

ix) A solution of 3.2 g (8.1 mmol) of N - [(9-fluorenyl) methoxycarbonyl] -3- (2-methylphenyl) -L-alanine and 2.17 g (6.75 mmol) 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate in 22 ml of dimethylformamide was added to the resin from section viii) and then 1.5 ml (13.5 mmol) N-methylmorpholine added. The mixture was 30 Mi agitated for minutes and then the resin was poured off and five times with 30 ml of dimethylformamide, twice with 30 ml Dichloromethane, twice with 30 ml of ethyl acetate and twice with Washed 30 ml of diethyl ether. After drying, 8.95 g 5- [4 - [[N- [N- [N - [(9-fluorenyl) methoxycarbonyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] -N- [3,3,3-trifluoro- 1 (RS) - (dimethoxymethyl) propyl] amino] methyl] -3,5-dimethoxy phenoxy] -N- (4-methyl-α- (RS) -phenylbenzyl) valeramide polysty rolkonjugat as a pale brown solid (0.31 mmol / g loading, estimated by quantitative evaluation of dibenzofulves at 301 nm).  

Example 2

In an analogous manner to that in Example 1, where N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N- [(9-Fluorenyl) methoxycarbonyl] -N6-nitro-L-arginine replaced 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α- aspartyl] -N6-nitro-L-arginyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 945.5 [M + H].

Example 3

In an analogous manner to that in Example 1, where N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N- [(9-Fluorenyl) methoxycarbonyl] -S- (acetamidomethyl) -L-cysteine was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropio nyl) -L-α-aspartyl] -S- (acetamidomethyl) -L-cysteinyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 918.4 [M + H].

Example 4

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -S-benzyl-L-cysteine was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspar tyl] -S-benzyl-L-cysteinyl] -2-methyl-L-phenylalanyl] -3-methyl- 3-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as obtained white solid; MS: m / e 937.4 [M + H].

Example 5

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -D-valine was replaced and N - [(9-  Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -S, S-dioxo-L-methionine was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropio nyl) -S, S-dioxo-L-net-hionyl] -D-valyl] -2-methyl-L-phenylala nyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde obtained as a white solid; MS: m / e 891.5 [M + H].

Example 6

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -D-valine was replaced and N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -S, S-dioxo-S-methyl-L- cysteine was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3- Carboxypropionyl) -S, S-dioxo-S-methyl-L-cysteinyl] -D-valyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 877.5 [M + H].

Example 7

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -D-valine was replaced and N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -1- (2,4-dinitrophenyl) - L-histidine was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3- Carboxypropionyl) -1- (2,4-dinitrophenyl) -L-histidyl] -D-valyl] - 2-methyl-L-phenylalanyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde obtained as a white solid; MS: m / e 1031.5 [M + H].

Example 8

In an analogous manner to that in Example 1, where N - [(9-fluorenyl) - methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9-  Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid with N - [(9-fluorenyl) methoxycarbonyl] -S-t-butyl-L-cysteine replaced 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L- cysteinyl] -D-valyl] -2-methyl-L-phenylalanyl] -3-methyl-L- valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as white Get solid; MS: m / e 887.5 [M + H].

Example 9

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -3- (3-thenyl) -D-alanine was replaced de, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α- aspartyl] -3- (3-thenyl) -D-alanyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: n / e 897.2 [M + H].

Example 10

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -D-N- (tert-butoxycarbonyl) trypto phan was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxy propionyl) -L-α-aspartyl] -D-tryptophyl] -2-methyl-L-phenylala nyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde obtained as a white solid; MS: m / e 930.4 [M + H].

Example 11

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-tyrosine was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspar tyl] -O-benzyl-D-tyrosyl] -2-methyl-L-phenylalanyl] -3-methyl-L- valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as white Get solid; MS: m / e 997.4 [M + H].  

Example 12

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -S- (4-methoxybenzyl) -D-cysteine 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropio nyl) -L-cx-aspartyl] -S- (4-methoxybenzyl) -D-cysteinyl] -2-me thyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4- Trifluorobutyraldehyde obtained as a solid; MS: m / e 967.3 [M + H].

Example 13

In an analogous manner to that in Example I, where N - [(9-fluorene nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspar tyl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L- valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as white Get solid; MS: n / e 921.3 [M + H].

Example 14

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-threonine was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -α-aspar tyl] -O-benzyl-D-threonyl] -2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as white obtained solid; MS: m / e 935.4 [M + H].

Example 15

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzylserine has been replaced and N-  [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 2- (2,4,6- Trimethylphenyl) acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [2- (2,4,6-trimethylphenyl) acetyl] -L-seryl] -O-benzyl- D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leu cyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid receive; MS: n / e 953.4 [M + H].

Example 16

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 4-chloro-3- sulfamoylbenzoic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (4-chloro-3-sulfamoylbenzoyl) -L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 1010.3 [M + H].

Example 17

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by Benzotria zol-5-carboxylic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [(IH-benzotriazol-5-yl) carbonyl-L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 938.4 [M + H].  

Example 18

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 4- (phenyl carbamoyl) butyric acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [4- (phenylcarbamoyl) butyryl] -L-seryl] -O-benzyl-D- seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid ten; MS: m / e 982.4 [M + H].

Example 19

In an analogous manner to that in Example I, where N - [(9-fluorene nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine and tert-butyl hydrogen succinate was replaced by 2 - [(4,6- Dimethyl-2-pyrinidinyl) thio] acetic acid was replaced 2 (RS) - [[N- [N- [N- [N- [N- [2 - [(4,6-dimethyl-2-pyrimidinyl) thio] acetyl] -L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 973.4 [M + H].

Example 20

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 2-chlorine  nicotinic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N - [(2- Chloro-3-pyridyl) carbonyl] -L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 932.3 [M + H].

Example 21

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 4-acet amidobenzoic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (4-acetamidobenzoyl) -L-seryl] -O-benzyl-D-seryl] -2-methyl-L- phenylalanyl] -3-methyl-L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde obtained as a white solid; MS: m / e 954.4 [M + H].

Example 22

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 9-hydroxy 9-fluorenylcarboxylic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N - [(9-hydroxy-9-fluorenyl) carbonyl] -L-seryl] -O-benzyl-D- seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid ten; MS: m / e 1001.3 [M + H].  

Example 23

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-F1uorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by dihydro-L- orotic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N - [(Hexa hydro-2,6-dioxo-4 (S) pyrimidinyl) carbonyl] -L-seryl] -O-benzyl- D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L- leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid receive; MS: m / e 933.4 [M + H].

Example 24

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 2-furoe acid was replaced, 2 (RS) - [[N-IN- [N- [N- [N- (2-furoyl) - L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as white obtained solid; MS: m / e 887.3 [M + H].

Example 25

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine and tert-butyl hydrogen succinate was replaced by 2 (RS) - (4- Nitrophenyl) propionic acid was replaced, 2 (RS) - [[N- [N-  [N- [N- [N- [2 (RS) - (4-nitrophenyl) propionyl] -L-seryl] -O-benzyl- D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L- leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid receive; MS: m / e 970.4 [M + H].

Example 26

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -L-leucine by N - [(9-fluorenyl) methoxy carbonyl] -O-benzyl-L-tyrosine was replaced and N - [(9-fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropio nyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -O-benzyl-L-tyrosyl] amino] -4,4,4-trifluoro Obtain butyraldehyde as a white solid; MS: m / e 1013.3 [M + H].

Example 27

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -L-leucine by N - [(9-fluorenyl) methoxy carbonyl] -O- (2,6-dichlorobenzyl) -L-tyrosine was replaced and N - [(9-fluorenyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-gluta minic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carb oxypropionyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenyl alanyl] -3-methyl-L-valyl] -O- (2,6-dichlorobenzyl) -L-tyrosyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid ten; MS: m / e 1081.2 [M + H].

Example 28

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -L-leucine by N - [(9-fluorenyl) methoxy carbonyl] -2- (3-thienyl) -L-alanine was replaced and N - [(9-  Fluorenyl) methoxycarbonyl] -O-benzyl-α-gluta 40240 00070 552 001000280000000200012000285914012900040 0002019914474 00004 40121minic acid by N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropio nyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3- methyl-L-valyl] -2- (3-thienyl) -L-alanyl] amino] -4,4,4-trifluoro Obtain butyraldehyde as a white solid; MS: m / e 913.4 [M + H].

Example 29

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 4- (2- Thenoyl) butyric acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [4- (2-Thenoyl) butyryl] -L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 973.4 [M + H].

Example 30

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-cx-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -N6-nitro-L-arginine was replaced, N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-asparagine acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L- serine was replaced and tert-butyl hydrogen succinate together with 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetra fluoroborate was replaced by acetic anhydride 2 (RS) - [[N- [N- [N- [N2- (N-acetyl-L-tyrosyl) -N6-nitro-L-arginyl] - 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 935.5 [M + H].  

Example 31

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 2- (2-chlorine phenyl) acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [2- (2-chlorophenyl) acetyl] -L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino- 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 945.4 [M + H].

Example 32

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 2-ethoxy acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (2- Ethoxyacetyl) -L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenyl alanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluoro Obtain butyraldehyde as a white solid; MS: m / e 879.4 [M + H].

Example 33

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl-L-serine and tert-butyl hydrogen  succinate replaced by 3-hydroxy-4,5-dimethoxybenzoic acid 2 (RS) - [[N- [N- [N- [N- [N- (3-hydroxy-4,5-dimethoxy benzoyl] -L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-ieucyl] amino] -4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 973.4 [M + H].

Example 34

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid replaced by N - [(9-fluorenyl) methoxycarbonyl] -O-t-L-serine was and tert-butyl hydrogen succinate by 2-ethyl butter acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (2-ethyl butyryl) -L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: n / e 891.4 [M + H].

Example 35

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-benzyl-D-serine has been replaced, N- [(9-Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-aspartic acid by N - [(9-fluorenyl) methoxycarbonyl] -O-t-butyl-L-serine was set and tert-butyl hydrogen succinate by 2- (3-fluoro 4-hydroxyphenyl) acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3-fluoro-4-hydroxyphenyl) acetyl] -L-seryl] -O-benzyl- D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L- leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid receive; MS: m / e 945.4 [M + H].  

Example 36

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 4- (4- Methylphenyl) butyric acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [4- (4-methylphenyl) butyryl] -L-α-aspartyl] -L-α-glu tamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid ten; MS: m / e 933.5 [M + H].

Example 37

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 3- (4-meth oxybenzoyl) propionic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [3- (4-Methylbenzoyl) propionyl-L-α-aspartyl] -L-α-gluta nyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] ami no] -4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 947.4 [M + H].

Example 38

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-butyl-L-α-glutamic acid replaced and tert-butyl hydrogen succinate by 2- (2-methoxy ethoxy) ethoxy] acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [2- [2- (2-methoxyethoxy) ethoxyacetyl] -L-α-aspar tyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L- valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as white Get solid; MS: m / e 933.4 [M + H].  

Example 39

In an analogous manner to that in Example 1, where N - [(9-fluorenyl) - methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid and tert-butyl hydrogen succinate was replaced by 2- (4-oxo-2- thioxo-3-thiazolidinyl) acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [2- (4-oxo-2-thioxo-3-thiazolidinyl) acetyl] -L- α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as white obtained solid; MS: m / e 946.3 [M + H].

Example 40

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 3- (2- Methyl-4-nitro-1-imidazolyl) propionic acid was replaced 2 (RS) - [[N- [N- [N- [N- [N- [3- (2-methyl-4-nitro-1-imidazolyl) pro pionyl] -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylala nyl] -3-methyl-L-valyl] -L-leucyl] -4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 954.4 [M + H].

Example 41

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 5- Hexic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (5- Hexinoyl) -L-α-aspartyl] -L-α-glutamyl] -L-phenylalanyl] -3- methyl-L-valyl] -L-leucyl] amino] amino] -3,3,3-trifluorobutyr aldehyde obtained as a white solid; MS: m / e 867.4 [M + H].  

Example 42

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 6-chino linincarboxylic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [(6-quinolyl) carbonyl] -L-α-aspartyl] -L-α-glutamyl] -2-methyl- L-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-butyraldehyde obtained as a white solid; MS: m / e 928.4 [M + H].

Example 43

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 6-oxo-3- pyranylcarboxylic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N - [(6-oxo-3-pyranyl) carbonyl] -L-α-aspartic acid] -L-α-glu tamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid ten; MS: m / e 895.4 [M + H].

Example 44

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 2- (1,3- Benzodioxol-5-yl) acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [2- (1,3-benzodioxol-5-yl) acetyl] -L-α-aspartyl] - L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L- leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid receive; MS: m / e 935.4 [M + H].  

Example 45

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 5.6- Dihydro-6,6-dimethyl-4-oxo-4H-pyran-2-yl-carboxylic acid replaced 2 (RS) - [[N- [N- [N- [N- [N - [(5,6-dihydro-6,6-dime thyl-4-oxo-4H-pyran-2-yl) carbonyl] -L-α-aspartyl] -L-α-gluta myl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid ten; MS: m / e 925.4 [M + H].

Example 46

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 2- (2- Naphthyl) acetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [2- (2-naphthyl) acetyl] -L-α-aspartyl] -L-α-glutamyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] - 4,4,4-trifluorobutyraldehyde obtained as a white solid; MS: m / e 941.4 [M + H].

Example 47

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 3-benzami dopropionic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3- Benzamidopropionyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-tri fluorobutyraldehyde obtained as a white solid; MS: m / e 948.4 [M + H].  

Example 48

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 1,2,3,4- Tetrahydro-2,4-dioxo-5-pyrimidinylcarboxylic acid was replaced, was 2 (RS) - [[N- [N- [N- [N- [N- (1,2,3,4-tetrahydro-2,4-dioxo-5- pyrimidinyl) carbonyl] -L-α-glutamyl] -2-methyl-L-phenylala nyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde obtained as a white solid; MS: m / e 911.4 [M + H].

Example 49

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 3-methyl-2- thenoic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (3- Methyl-2-thenoyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-tri fluorobutyraldehyde obtained as a white solid; MS: m / e 897.4 [M + H].

Example 50

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid was set and tert-butyl hydrogen succinate by 2-cyclo hexylacetic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- (2-cyclohexylacetyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-tri fluorobutyraldehyde obtained as a white solid; MS: m / e 897.5 [M + H].  

Example 51

In an analogous manner to that in Example 1, where N - [(9-Fluore nyl) methoxycarbonyl] -O-benzyl-α-glutamic acid by N - [(9- Fluorenyl) methoxycarbonyl] -O-t-butyl-L-α-glutamic acid and tert-butyl hydrogen succinate was replaced by 2 (RS) - (4- Nitrophenyl) propionic acid was replaced, 2 (RS) - [[N- [N- [N- [N- [N- [2- (RS) - (4-nitrophenyl) propionyl] -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L- leucyl] amino] -4,4,4-trifluorobutyraldehyde as a white solid receive; MS: m / e 950.3 [M + H].

Example 52

4 g 0.25 mmol / g 5- [2- [1 (RS) - [[N- [9-fluorenyl) methoxycarbo nyl] -L-leucyl] amino] propyl-4 (RS), 5,5-trimethyl-1,3,2-dioxobo rolan-4-yl] -3 (RS) -methyl-N- [α (RS) - (4-methylphenyl) benzyl] valeramide-polystyrene conjugate was made in dimethylformamide 20 Swollen for minutes and then in dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin became poured off and then again in dimethylformamide / piperidine (4: 1) suspended and stirred for a further 5 minutes. The Resin was then poured off and five times with dimethylformamide washed.

The resin was dissolved in a solution of 2.1 g (6 mmol) N - [(9- Fluorenyl) methoxycarbonyl] -3-methyl-L-valine in dimethylforma mid suspended and then a mixture of 1.9 g of 2- (1H- Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate and 1.3 ml of N-methylmorpholine, dissolved in dimethylformamide given. After stirring for 40 minutes, the resin was poured off and washed five times with dimethylformamide.

The resin was suspended in dimethylformamide / piperidine (4: 1) dated and stirred. After 5 minutes the resin was poured off and again in dimethylformamide / piperidine (4: 1) another 5 mi  suspended and stirred for several minutes. Then the resin was removed poured and washed five times with dimethylformamide.

The resin was dissolved in a solution of 2.4 g (6 mol) of N - [(9- Fluorenyl) methoxycarbonyl] -3- (2-methylphenyl) -L-alanine in Di methylformamide suspended and then a mixture of 1.9 g of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate and 1.3 ml of N-morpholine, dissolved in dimethyl formamide, added. After stirring for 40 minutes, the resin poured off and washed five times with dimethylformamide.

40 mg of the Har obtained according to the previous section zes were suspended in 0.7 ml of dimethylformamide / piperidine (4: 1) dated and stirred. After 5 minutes the resin was poured off and again in dimethylformamide / piperidine (4: 1) another 5 mi suspended and stirred for several minutes. Then the resin was removed poured and washed five times with dimethylformamide.

The resin was dissolved in 0.5 ml of a 0.2 M solution of N - [(9- Fluorenyl) methoxycarbonyl] -L-glutamic acid γ-benzyl ester in Dimethyl sulfoxide and then 0.5 ml of a mixture from 0.2 M 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluro nium tetrafluoroborate and 0.4 M N-methylmorpholine in dimethyl formamide added. After stirring for one hour, the resin poured off and washed five times with 1 ml of dimethylformamide.

The resin was again in 0.7 ml dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin became poured off and again in dimethylformamide / piperidine (4: 1) suspended and stirred for a further 5 minutes. Then was the residue was poured off and five times with 1 ml of dimethyl form amide washed.

The resin was dissolved in 0.5 ml of a 0.2 M solution of 1- (2,4- Dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine in Dimethyl sulfoxide and then 0.5 ml of a Mi  was made from 0.2 M 2- (IH-benzotriazol-1-yl) -1,1,3,3-tetrame thyluronium tetrafluoroborate and 0.4 M N-methylmorpholine, ge dissolves in dimethylformamide, added. After stirring for one hour the resin was poured off and five times with 1 ml of dimethyl form amide washed.

The resin was again in 0.7 ml dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin became poured off and again in dimethylformamide / piperidine (4: 1) suspended and stirred for a further 5 minutes. Then was the residue was poured off and five times with 1 ml of dimethyl form amide washed.

The resin was dissolved in 0.5 ml of a 0.2 M solution of acetic acid hydride suspended in dimethylformamide and then 0.5 ml of one Mixture of 0.2 M 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetrame thyluronium tetrafluoroborate and 0.4 M N-methylmorpholine, ge dissolves in dimethylformamide, added. After stirring for one hour the resin was poured off and five times with 1 ml of dimethyl form amide and then washed twice with 1 ml dichloromethane.

0.2 ml of dichloromethane was added to the residue which then 0.7 ml of trifluoroacetic acid / water (19: 1) was added and stirred for 90 minutes. The residue was filtered off and with 0.7 ml trifluoroacetic acid / water (19: 1) washed. The combined trifluoroacetic acid / water solutions were then evaporated in a vacuum centrifuge and the back was suspended in acetonitrile / water and freeze-dried net. 8 mg of 1 (RS) - [N- [N- [N- [N-acetyl-1- (2,4-dinitro phenyl) -L-histidyl] -O-benzyl-L-α-glutamyl] -2-methyl-L-phe nylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained as a white solid; MS: m / e 888.5 [M + H-167] ⁺.

The starting material was produced as follows:

i) 25 ml of isobutylene were condensed at -78 ° C. and added to a mixture of 19.4 g (114 mmol) of 3 (RS) -7-dimethyl-6-octenoic acid and 1 ml of concentrated sulfuric acid in 25 ml of dichloromethane. The mixture was stirred under a dry ice cooler for 24 hours. Another 20 ml of isobutylene was added and the mixture was stirred under a dry ice cooler for a further 24 hours. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The remaining oil was purified by chromatography on silica gel using ethyl acetate / hexane (1: 9) for the elution. 20.8 g of tert-butyl-3 (RS), 7-dimethyl-6-octenoate were obtained as a colorless oil.
¹ H-NMR: (250 MHz, CDCl ₃ ) δ: 0.9 (d, 3H), 1.1-1.3 (m, 3H), 1.4 (s, 9H), 1.6 (s , 3H), 1.65 (s, 3H), 1.8-2.2 (br in, 4H), 5.05 (m, 1H).

ii) 1.5 g (6.64 mmol) of tert-butyl-3 (RS), 7-dimethyl-6-octenoate were in a mixture of 10 ml of acetone, 2 ml of water and 2 ml of glacial acetic acid dissolved. 2 g (12.6 mmol) of potassium permanganate were added and the resulting mixture at 30 ° C for 2 hours long stirred. 22 ml of 2 M sulfuric acid and 0.8 g (11.3 mmol) Sodium nitrite was added and the organic phase removed separates. The aqueous phase was extracted with dichloromethane and washed the combined organic phases with water, dried over magnesium sulfate and evaporated in vacuo, which was 1.55 g of tert-butyl-7-hydroxy-3 (RS), 7-dimethyl-6-oxo-octe gave noat as a clear oil; MS: m / e 259 [M + H] ⁺.

iii) 0.25 g (0.97 mmol) of tert-butyl-7-hydroxy-3 (RS), 7-dime thyl-6-oxo-octenoate were in 3 ml of diethyl ether at 0 ° C under Dissolved nitrogen atmosphere. 0.36 ml (1.1 mmol) 3 M methyl Magnesium bromide in diethyl ether was added dropwise and stirring the resulting solution at 0 ° C for 2 hours, 6 Held at reflux for hours and then at room temperature Stirred for 16 hours. The solution was washed with ethyl acetate diluted and then with 2 M hydrochloric acid and with saturated Na extracted trium chloride solution. The organic phase was  dried over anhydrous sodium sulfate and in a vacuum steamed. The resulting oil was broken up by chromatography Purified silica gel, using ethyl acetate / hexane (1: 2) for the Elution was used. 118 mg of tert-butyl 6 (RS), 7-dihydroxy-3 (RS), 6,7-trimethyl-6-octenoate as clear Get oil; MS: m / e 275 [M + H] ⁺.

iv) 0.64 g (2.3 mmol) tert-butyl-6 (RS), 7-dihydroxy- 3 (RS), 6,7-trimethyl-6-octenoate were dissolved in 3 ml of tetrahydrofuran and 0.5 g (2.5 mmol) dichloromethyldiisopropoxyborane at room temperature stirred for 16 hours. The resulting mixture was evaporated and the residue co-evaporated with toluene evaporated to give 0.86 g of tert-butyl-5- [2- (dichloromethyl) -4 (RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) methylvale advice as oil, which in the next stage without further Cleaning was used.

v) 0.86 g (2.3 mmol) of tert-butyl-5- [2- (dichloromethyl) -4 (RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) methylvale rat were dissolved in 5 ml of tetrahydrofuran and the solution -78 ° C cooled under a nitrogen atmosphere. 2.6 ml (2.6 mmol) 1 M ethyl magnesium bromide in tetrahydrofuran was added dropwise added wise, the resulting solution for 16 hours stirring, slowly warming to room temperature, and then diluted with ethyl acetate and with 2 M hydrochloric acid and cook extracted saline. The organic phase was over natri dried sulfate and then concentrated under vacuum, which was 0.83 g of tert-butyl-5- [2- (1 (RS) -chloropropyl) -4 (RS), 5.5- trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) methylvalerate as an oil delivered that used in the next stage without cleaning has been.

vi) 0.82 g (2.27 mmol) of tert-butyl-5- [2- (1 (RS) -chloropropyl) - 4 (RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) -methylva Ierate were dissolved in 10 ml of tetrahydrofuran and then dissolved -78 ° C cooled under a nitrogen atmosphere. 2.3 ml (2.3 mmol)  1 M Lithium bis (trimethylsilyl) amide in tetrahydrofuran were added dropwise. The solution was then overnight stirring, slowly warming to room temperature. The solvent was removed by evaporation and the Residue taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate to 0 ° C cools. 0.52 ml (6.8 mmol) trifluoroacetic acid was added and the solution was stirred at 0 ° C for 30 minutes. The solution was evaporated and the residue along with toluene evaporated, giving 1 g of tert-butyl-5- [2- (1 (RS) -aminopropyl) - 4 (RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) -methylva lerat as oil, which in the next stage without Reini was used.

vii) 0.5 g (1.42 mmol) N - [(9-fluorenyl) methoxycarbonyl] -L- leucine was dissolved in 7 ml dichloromethane. 0.6 ml (5.7 mmol) N-methylmorpholine was added and the solution under Nitrogen atmosphere cooled to -10 ° C. 0.22 ml (1.7 mmol) Isobutyl chloroformate was added and the solution 7 min stirred at -10 ° C. 1 g (2.13 mmol) tert-butyl-5- [2- (1 (RS) aminopropyl) -4 (RS), 5,5-trimethyl-1,3,2-dioxaborolan-4- yl] -3 (RS) methylvalerate was added and the mixture at Stir room temperature for 16 hours, then with dichlor diluted methane and extracted with 2 M hydrochloric acid. The organi phase was washed with 2 M hydrochloric acid and saturated sodium hy bicarbonate solution extracted and then over anhydrous Magnesium sulfate dried. After evaporation, the Residue purified by chromatography on silica gel where with ethyl acetate / hexane (1: 2) was used for the elution. 0.56 g of tert-butyl-5- [2- [1 (RS) - [[N - [(9-fluorenyl) methoxycarbonyl] -L-leucyl] amino] amino] propyl] -4 (RS), 5,5-tri methyl-1,3,2-dioxaborolan-4-yl] -3 (RS) methylvalerate as an oil receive; MS: m / e 677 [M + H] ⁺.

viii) 50 mg (0.074 mmol) tert-butyl-5- [2- [1 (RS) - [[N - [(9- fluorenyl) methoxycarbonyl] -L-leucyl] amino] propyl] -4 (RS), 5.5-  trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) methylvalerate dissolved in 1 ml trifluoroacetic acid and 1 ml dichloromethane. The Solution was stirred at room temperature for 15 minutes and then evaporated in vacuo. The backlog was along with Toluene evaporated, giving 46 mg 5- [2- [1 (RS) - [[N - [(9-fluorenyl) - methoxycarbonyl] -L-leucyl] amino] propyl] -4 (RS), 5,5-trimethyl- 1,3,2-dioxaborolan-4-yl] -3 (RS) -methylvaleric acid as an oil delivered; MS: m / e 621 [M + H] ⁺.

ix) 5 g (5.25 mmol) of 4-methylbenzhydrylamine resin were dissolved in Di methylformamide swollen and excess solvent was poured out of the resin. The resin was then in dime thylformamide, the 3.4 g (5.48 mmol) 5- [2- [1 (RS) - [[N - [(9- fluorenyl) methoxycarbonyl] -L-leucyl] amino] propyl] -4 (RS), 5.5- trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) methylvaleric acid and 3 g (8.2 mmol) of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetra contained methyluronium hexafluorophosphate, suspended. It was added to the 3.0 ml (16.5 mmol) diisopropylamine. The first The mixture was stirred for 100 minutes and the resin then poured off and washed three times with dimethylformamide. The resin was then returned to dimethylfarmamide containing 5 ml (54.8 mmol) acetic anhydride and 11.5 ml (110 mmol) Contained N-methylmorpholine, suspended. The mixture was Stirred for 30 minutes and then poured the resin. The Resin was then returned to dimethylformamide containing 5 ml (54.8 mmol) acetic anhydride and 11.5 ml (110 mmol) N-methyl morpholine contained, suspended. The mixture was 30 minutes stirred for ten and then poured the resin and three times with Dimethylformamide, twice with ethyl acetate, twice with Dichloromethane and washed twice with diethyl ether and then dried in vacuo. After drying, 6 g of 5- [2- [1 (RS) - [[N - [(9-fluorenyl) methoxycarbonyl] -L-leucyl] amino] pro pyl] -4- (RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl] -3 (RS) methyl-N- (RS) - (4-methylphenyl) benzyl] valeramide polystyrene Conjugate obtained as a pale brown solid (0.25 mmol / g Be  charge, estimated by quantitative evaluation of diben zofulven at 301 nM).

Example 53

In an analogous manner to that described in Example 52, where N- [(9-Fluorenyl) methoxycarbonyl] -L-glutamic acid γ-benzyl ester by N - [(9-fluorenyl) methoxycarbonyl] -N6- (p-toluenesulfonyl) - L-arginine was replaced, 1 (RS) - [[N- [N- [N- [N2- [N-acetyl- 1- (2,4-dinitrophenyl) -L-histidyl] -N6- (p-toluenesulfonyl) -L-ar ginyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained as a white solid; MS: m / e 980.3 [M + H-167] ⁺.

Example 54

In an analogous manner to that described in Example 52, replacing N- [(9-fluorenyl) methoxycarbonyl] -L-glutamic acid γ-benzyl ester with N - [(9-fluorenyl) methoxycarbonyl] -O-benzyl-D-tyrosine 1 (RS) - [[N- [N- [N- [N- [N- [N-acetyl-1- (2,4-di nitrophenyl) -L-histidyl] -O-benzyl-D-tyrosyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained as a white solid; MS: m / e 905.5 [M + HH ₂ O-167] ⁺.

Example 55

In an analogous manner to that described in Example 52, where N- [(9-fluorenyl) methoxycarbonyl] -L-glutamic acid γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxycarbonyl] -4-nitro-D-phenylalanine , 1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-di nitrophenyl) -L-histidyl] -4-nitro-D-phenylalanyl] - 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained as a white solid; MS: m / e 844.4 [M + HH ₂ O 167] ⁺.

Example 56

In an analogous manner to that described in Example 52, where N- [(9-fluorenyl) methoxycarbonyl] -L-glutamic acid γ-benzyl ester is replaced by N - [(9-fluorenyl) methoxycarbonyl] -O-benzyl-D-serine 1 (RS) - [[N- [N- [N- [N- [N- [N-acetyl-1- (2,4-di nitrophenyl) -L-histidyl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained as a white solid; MS: m / e 829.5 [M + HH ₂ O-167] ⁺.

Example 57

In an analogous manner to that described in Example 52, replacing N- [(9-fluorenyl) methoxycarbonyl] -L-glutamic acid γ-benzyl ester with N - [(9-fluorenyl) methoxycarbonyl] -L-2-cyclohexylglycine 1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -L-2-cyclohexylglycyl] -2-methyl-L - phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained as a white solid; MS: m / e 751.5 [M + HH ₂ O- 167] ⁺.

Example 58

In a manner analogous to that described in Example 52, where N- [(9-fluorenyl) methoxycarbonyl] -L-glutamic acid γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxycarbonyl] -D-2-phenylglycine, was 1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-di nitrophenyl) -L-histidyl] -D-2-phenylglycyl] -2-methyl -L-phenyl alanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained as a white solid; MS: m / e 791.5 [M + HH ₂ O-167] ⁺.

Example 59

In an analogous manner to that described in Example 52, where 1- (2,4-dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine through N - [(9-fluorenyl) methoxycarbonyl] -O- benzyl-L-serine was replaced and N - [(9-fluorenyl) methoxycarbonyl] -L-glutaminic acid-γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxycarbononyl] -N6-nitro-L-arginine, was 1 (RS) - [[N- [N- [N- [N2- [N-acetyl-O-benzyl-L-seryl] -N6-nitro-L-arginyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid obtained; MS: m / e 893.5 [M + HH ₂ O] ⁺.

Example 60

In an analogous manner to that described in Example 52, where 1- (2,4-dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine through N - [(9-fluorenyl) methoxycarbonyl] -O- benzyl-L-serine was replaced and N - [(9-fluorenyl) methoxycarbonyl] -L-glutaminic γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxycarbononyl] -S-benzyl-L-cysteine, was 1 (RS) - [[N- [N- [N- [N- [N- (N-acetyl-O-benzyl-L-seryl) -S-benzyl-L-cysteinyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] -L-leucyl] amino] propyl boronic acid obtained; MS: m / e 885.5 [M + HH ₂ O] ⁺

Example 61

In an analogous manner to that described in Example 52, where 1- (2,4-dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine through N - [(9-fluorenyl) methoxycarbonyl] -O- benzyl-L-serine was replaced and N - [(9-fluorenyl) methoxycarbonyl] -L-glutaminic acid-γ-benzyl ester was replaced by 1-tert-butoxycarbonyl-N - [(9-fluorenyl) methoxycarbonyl] -D-tryptophan was 1 (RS) - [[N- [N- [N- [N- [N- (N-acetyl-O-benzyl-L-seryl) -D-tryptophyl] - 2-methyl-L-phenylalanyl] -3 -methyl-L-valyl] -L-leucyl] amino] propylboronic acid; MS: m / e 875.8 [M + HH ₂ O] ⁺.

Example 62

In an analogous manner to that described in Example 52, where 1- (2,4-dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine through N - [(9-fluorenyl) methoxycarbonyl] -O- benzyl-L-serine was replaced and N - [(9-fluorenyl) methoxycarbonyl] -L-glutaminic acid-γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxycarbononyl] -D-valine, 1 (RS ) - [[N- [N- [N- [N- (N-acetyl-O-benzyl-L-seryl) -D-valyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl ] -L-leucyl] amino] propylboronic acid obtained; MS: m / e 791.5 [M + HH ₂ O] ⁺.

Example 63

In an analogous manner to that described in Example 52, where 1- (2,4-dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine by N - [(9-fluorenyl) methoxycarbonyl] -S, S-dioxo-L-methionine was replaced and N - [(9-fluorenyl) methoxycarbonyl] - L-glutamic acid-γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxy carbonyl] -N6-nitro-L-arginine , 1 (RS) - [[N- [N- [N- [N2- (N-acetyl-S, S-dioxo-L-methionyl) -N6-nitro-L-arginyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amine no] propylboronic acid; MS: n / e 879.5 [M + HH ₂ O] ⁺.

Example 64

In an analogous manner to that described in Example 52, where 1- (2,4-dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine through N - [(9-fluorenyl) methoxycarbonyl] -O- tert-butyl-L- (α-aspartic acid was replaced and N - [(9-fluorenyl) methoxy carbonyl] -L-glutamic acid-γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxycarbonyl] -S, S- dioxo-L-methionine was replaced, 1 (RS) - [[N- [N- [N- [N- (N-acetyl-L-α-aspartyl) -S, S-dioxo-L-methionyl] - Obtained 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid as a white solid, MS: m / e 793.4 [M + HH ₂ O] ⁺.

Example 65

In an analogous manner to that described in Example 52, where 1- (2,4-dinitrophenyl) -N - [(9-fluorenyl) methoxycarbonyl] -L-histidine through N - [(9-fluorenyl) methoxycarbonyl] -O- tert.-butyl-L-α-aspartic acid was replaced and N - [(9-fluorenyl) methoxy carbonyl] -L-glutamic acid-γ-benzyl ester was replaced by N - [(9-fluorenyl) methoxycarbonyl] -S - [(acetamido ) methyl] -L-cysteine was replaced, 1 (RS) - [[N- [N- [N- [N- (N-acetyl-L-α-aspartyl) -S- [(acetamido) methyl] - L-cysteinyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid was obtained as a white solid; MS: m / e 804.4 [M + HH ₂ O] ⁺.

Example 66

4 g 0.25 mmol / g 5- [2- [1 (RS) - [[N - [(9-fluorenyl) methoxycarbo nyl] -L-leucyl] amino] propyl] -4 (RS), 5,5-trimethyl-1,3,2-dioxa borolan-4-yl] -3 (RS) -methyl-N- [α (RS) - (4-methylphenyl) benzyl] valeramide-polystyrene conjugate (prepared as in example 52) were in dimethylformamide for 20 minutes swollen and then in dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin was removed poured and then again in dimethylformamide / piperidine (4: 1) suspended and stirred for a further 5 minutes. The resin was de then poured off and washed five times with dimethylformamide .

The resin was then dissolved in a solution of 2.1 g (6 mmol) of N - [(9- Fluorenyl) methoxycarbonyl] -3-methyl-L-valine in dimethylforma mid suspended and then a mixture of 1.9 g of 2- (1H- Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate and 1.3 ml (0.12 mmol) of N-methylmorpholine dissolved in dimethyl formamide, added. After stirring for 40 minutes, the resin poured off and washed five times with dimethylformamide.

The resin was again in dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin was removed poured and again in dimethylformamide / piperidine (4: 1) more Suspended and stirred for 5 minutes. Then the resin poured off and washed five times with 1.5 ml of dimethylformamide.  

The resin was then dissolved in a solution of 2.4 g (6 mmol) of N - [(9- Fluorenyl) methoxycarbonyl] -3- (2-methylphenyl) -L-alanine in Di suspended methylformamide and then a mixture of 1.9 g 2- (1H-Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetra fluoroborate and 1.3 g of N-methylmorpholine, dissolved in dimethyl formamide, added. After stirring for 40 minutes, the resin poured off and washed five times with dimethylformamide.

40 mg of this resin were dissolved in 0.7 ml dimethylformamide / Piperidine (4: 1) resuspended and stirred. After 5 minutes The resin was poured off and again in dimethyl form amide / piperidine (4: 1) suspended for a further 5 minutes and touched. Then the resin was poured off and five times with dime washed thylformamide.

The resin was then dissolved in 0.5 ml of a 0.2 M solution of N - [(9- Fluorenyl) methoxycarbonyl] -O-tert-butyl-L-α-glutamic acid suspended in dimethyl sulfoxide and then 0.5 ml of a Mi 0.2 M 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetrame thyluronium tetrafluoroborate and 0.4 M N-methylmorpholine in Di added methylformamide. After stirring for one hour, it became Poured resin and washed five times with 1 ml of dimethylformamide .

The resin was again in 0.7 ml dimethylformamide / piperidine (4: 1) suspended and stirred. After 5 minutes the resin became poured off and again in dimethylformamide / piperidine (4: 1) suspended and stirred for a further 5 minutes. Then was poured the resin and five times with 1 ml of dimethylformamide to wash.

The resin was then dissolved in 0.5 ml of a 0.2 M solution of N - [(9- Fluorenyl) methoxycarbpnyl] -O-tert-butyl-L-α-aspartic acid suspended in dimethyl sulfoxide and then 0.5 ml of a Mi 0.2 M 2- (1H-benzotriazol-l-yl) -1,1,3,3-tetrame thyluronium tetrafluoroborate and 0.4 M N-methylmorpholine in Di  added methylformamide. After stirring for one hour, it became Poured resin and washed five times with 1 ml of dimethylformamide .

The resin was then poured into 0.7 ml of dimethylformamide / piperidine (4: 1) resuspended and stirred. After 5 minutes it was poured the resin and again in dimethylformamide / piperidine (4: 1) suspended and stirred for a further 5 minutes. Then the resin was poured off and five times with 1 ml of dimethyl form amide washed.

The resin was dissolved in 0.5 ml of a 0.2 M solution of cumalic acid suspended in dimethylformamide and then 0.5 ml of a Mi 0.2 M 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetrame thyluronium tetrafluoroborate and 0.4 M N-methylnorpholine in Di added methylformamide. After stirring for one hour, it became Poured resin and five times with 1 ml of dimethylformamide and then washed twice with 1 ml dichloromethane.

0.2 ml of dichloromethane was added to the resin, which was then mixed with 0.7 ml of trifluoroacetic acid / water (19: 1) and then stirred for 90 minutes. It was then filtered off and washed with 0.7 ml trifluoroacetic acid / water (19: 1). The combined trifluoroacetic acid / water mixtures were then evaporated in a vacuum centrifuge and the residue was suspended in acetonitrile / water (1: 1) and freeze-dried. 7 mg 1 (RS) - [[N- [N- [N- [N- [N- (6-oxo-6H-pyran-3-yl) carbonyl] -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] aminoj propylboronic acid; MS: m / e 839.4 [M + HH ₂ O] ⁺.

Example 67

In an analogous manner to that in Example 66, where cumalic acid was replaced by 4-acetamidobutanoic acid, 1 (RS) - [[N- [N- [N- [N- [N- (4-acetamidobutyryl) -L-α- aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amine no] propylboronic acid; MS: m / e 844.5 [M + HH ₂ O] ⁺.

Example 68

In an analogous manner to that in Example 66, where cumalic acid was replaced by acetoxyacetic acid, 1 (RS) - [[N- [N- [N- [N- [N- [N- (2-acetoxyacetyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propyl boronic acid; MS: m / e 817.5 [M + HH ₂ O] ⁺.

The following examples illustrate pharmaceutical preparations the compounds of the formula I contain:

Example A

Tablets containing the following ingredients can be made in the usual way:

Example B

Capsules containing the following ingredients can be made in the usual way:

Claims (33)

1. Compounds of the general formula
wherein
E represents -CHO or -B (OH) ₂ ;
R ^{1 represents} a lower alkyl, halogeno lower alkyl, cyano lower alkyl, lower alkylthio lower alkyl, aryl lower alkylthio lower alkyl, aryl lower alkyl, heteroaryl lower alkyl, lower alkenyl or lower riginyl group;
R ^{2 represents} R ^2a or R ^2b ;
R ^{2a represents} a lower alkyl, hydroxy lower alkyl, carboxy lower alkyl, aryl lower alkyl, aminocarbonyl lower alkyl or lower cycloalkyl lower alkyl radical;
R ^{2b represents} an aryl-lower alkoxy-aryl-lower alkyl or heteroaryl-lower alkyl radical;
R ^{3 represents} hydrogen or a lower alkyl radical or
R ² and R ³ together denote a di- or trimethylene radical, which is optionally substituted with hydroxyl radicals;
R ^{4 represents} lower alkyl, hydroxy lower alkyl, lower cycloalkyl lower alkyl, carboxy lower alkyl, aryl lower alkyl, lower alkylthio lower alkyl, cyano lower alkylthio lower alkyl, aryl lower alkylthio lower alkyl, lower alkenyl, aryl, or lower cyclo ;
R ^{5 represents} R ^5a or R ^5b ;
R ^{5a means} a lower alkyl, hydroxy lower alkyl, lower alkylthio lower alkyl, aryl lower alkyl, aryl lower alkylthio lower alkyl, cyano lower alkyl thio lower alkyl or lower cycloalkyl radical;
R ^{5b represents} a lower cycloalkyl lower alkyl radical;
R ^{6 represents} hydrogen or a lower alkyl radical;
R ^{7 represents} R ^7a or R ^7b ;
R ^{7a means} a lower alkyl, hydroxy lower alkyl, carboxy lower alkyl, aryl lower alkyl, lower cycloalkyl lower alkyl or lower cycloalkyl radical;
R ^{7b is} an aryl-lower alkylthio-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, aryl-lower alkylcarbonyl-lower alkyl, nitroguanidino-lower alkyl, aryl sulfonylguanidino-lower alkyl, lower alkyl sulfo , Acetamidomethylthio-lower alkyl, aryl or heteroaryl-lower alkyl means meaning;
R ^{8 represents} R ^8a or R ^3b ;
R ^{8a represents} a lower alkyl, hydroxy lower alkyl, carboxy lower alkyl or aryl lower alkyl radical;
R ^{8b represents} a mercapto lower alkyl, lower alkyl sulfonyl lower alkyl, aryl lower alkoxy lower alkyl or aryl heteroaryl lower alkyl group;
R ^{9 represents} R ^9a or R ^9b ;
R ^9a denotes a lower alkylcarbonyl, carboxy lower alkylcarbonyl, arylcarbonyl, lower alkylsulfonyl, aryl sulfonyl, lower alkoxycarbonyl, or aryl lower rigalkoxycarbonyl radical and
R ^{9b is} an aryl-lower alkylcarbonyl-, heteroaryl-lower rigalkylcarbonyl-, arylaminocarbonyl-lower alkyl carbonyl-, heteroarylthio-lower alkylcarbonyl-, he teroarylcarbonyl-, hydroxyfluorenylcarbonyl-, he teroarylcarbonyl-lower alkylcarbonyl-, lower alkyloxyyl, lower alkylcarbonyl-, lower alkylcarbonyl-, lower alkylcarbonyl-, loweralkyl Lower alkoxy lower alkoxy lower alkoxy lower alkylcarbonyl, arylcarbonylamino lower alkylcarbonyl, lower cycloalkyl lower alkylcarbonyl, lower alkylcarbonyl lower cyclo alkyl lower alkylcarbonyl, lower alkylcarbonyl amino lower alkylcarbonyl, heterocyclylcarbonyloxy, lower alkylcarbonyl, lower alkylcarbonyl - Lower alkylcarbonyl, lower alkynylcarbonyl or lower cycloalkylcarbonyl radical;
with the proviso that R ² , R ⁵ , R ⁷ , R ⁸ and R ⁹ do not simultaneously mean R ^2a , R ^5a , R ^7a , R ^8a and R ^9a ;
and salts of acidic compounds of the formula I with bases. 2. Compounds of the general formula
wherein E, R ¹ , R ^2b , R ³ , R ⁴ , R ^5a , R ⁶ , R ^7a , R ^8a and R ^{9a have} the meanings given in claim 1. 3. Compounds of the general formula
wherein E, R ¹ , R ^2a , R ³ , R ⁴ , R ^5a , R ⁶ , R ^7b , R ^8a and R ^{9a have} the meanings given in claim 1. 4. Compounds of the general formula
wherein E, R ¹ , R ^2a , R ³ , R ⁴ , R ^5a , R ⁶ , R ^7b , R ^8b and R ^{9a have} the meanings given in claim 1. 5. Compounds of the general formula
wherein E, R ¹ , R ^2a , R ³ , R ⁴ , R ^5a , R ⁶ , R ^7a , R ^8b and R ^{9a have} the meanings given in claim 1. 6. Compounds of the general formula
wherein E, R ¹ , R ^2a , R ³ , R ⁴ , R ^5a , R ⁶ , R ^7a , R ^8a and R ^{9b have} the meanings given in claim 1. 7. Compounds of the general formula
wherein E, R ¹ , R ^2a , R ³ , R ⁴ , R ^5a , R ⁶ , R ^7b , R ^8a and R ^{9b have} the meanings given in claim 1. 8. Compounds according to any one of claims 1 to 7, wherein R ^{1 means} a lower alkyl or halogeno lower alkyl radical. 9. Compounds according to claim 8, wherein R ^{1 is} a fluorine low rigalkylrest. 10. Compounds according to claim 1 or one of claims 3 to 9, wherein R ^{2 represents} a lower alkyl radical. 11. Compounds according to any one of claims 1 to 10, wherein R ^{3 is} hydrogen. 12. Compounds according to any one of claims 1 to 11, wherein R ^{4 represents} a lower alkyl radical. 13. Compounds according to any one of claims 1 to 12, wherein R ^{5 represents} an aryl-lower alkyl radical. 14. Compounds according to any one of claims 1 to 13, wherein R ^{6 is} hydrogen. 15. Compounds according to any one of claims 1, 2, 5, 6 and 8 to 14, wherein R ^{7a represents} a lower alkyl, carboxy, lower alkyl, aryl lower alkyl, lower cycloalkyl, lower alkyl or lower cycloalkyl radical. 16. Compounds according to any one of claims 1, 3, 4 and 7 to 14, wherein R ^{7b is} a nitroguanidino-lower alkyl, acet amidomethylthio-lower alkyl or lower alkylsulfonyl-lower alkyl radical. 17. Compounds according to any one of claims 1, 2, 3 and 6 to 16, wherein R ^{8a represents} a carboxy-lower alkyl, hydroxy-lower alkyl or aryl-lower alkyl radical. 18. Compounds according to any one of claims 1, 4, 5 and 8 to 16, wherein R ^{8b is} an aryl heteroaryl-lower alkyl be. 19. Compounds according to any one of claims 1 to 5 and 8 to 18, wherein R ^{9a represents} a lower alkylcarbonyl, carboxy, lower alkylcarbonyl or arylcarbonyl radical. 20. Compounds according to any one of claims 1 and 6 to 18, wherein R ^{9b is} a heteroarylcarbonyl, hydroxyfluoronylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl or aryl-lower alkylcarbonyl radical. 21. A compound of formula IA as set out in claim 2 selected from:
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -O-benzyl-L-tyrosyl] amino] -4,4,4-trifluorobutyr aldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -O- (2,6-dichlorobenzyl) -L-tyrosyl] amino] -4,4,4-trifluorobutyraldehyde and
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -2- (3-thienyl) -L-alanyl] amino] -4,4,4-trifluoro butyraldehyde. 22. A compound of formula IB as set out in claim 3 selected from:
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-L-α-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -N6-nitro-L-arginyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -S- (acetamidomethyl) -L-cysteinyl] -2-methyl- L-phenyl alanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-tri fluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -S-benzyl-L-cysteinyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -3- (3-thenyl) -D-alanyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -D-tryptophyl] -2-methyl-L-phenylalanyl] -3 -methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-D-tyrosyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -S- (4-methoxybenzyl) -D-cysteinyl] -2- methyl-L-phenyl alanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-tri fluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-D-seryl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -L-α-aspartyl] -O-benzyl-D-threonyl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (4-chloro-3-sulfamoylbenzoyl) -L-seryl)] - O-benzyl-D-seryl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [N- (4-acetamidobenzoyl) -L-seryl)] - O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-Hydroxy-4,5-dimethoxybenzoyl) - L-seryl)] - O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyr aldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (2-ethylbutyryl) -L-seryl)] - O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
1 (RS) - [[N- [N- [N- [N- (N-acetyl-L-α-aspartyl) -S, S-dioxo-L-methionyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid and
1 (RS) - [[N- [N- [N- [N- [N- (N-acetyl-L-α-aspartyl) -S - [(acetami do) methyl] -L-cysteinyl] -2-methyl-L -phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid. 23. A compound of formula IC as set out in claim 4 selected from:
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-L-α-glutamyl] -2 -methyl-L-phenylalynyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N2- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-N6- (p-toluenesulfonyl) - L-arginyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-I- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-D-tyrosyl] -2-methyl -L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -4-nitro-D-phenylalanyl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -O-benzyl-D-seryl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -D-2-phenylglycyl] -2-methyl-L -phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N2- [N-acetyl-O-benzyl-L-seryl] nitro-L-arginyl] -2-methyl-L-phenylalanyl] -3-methyl -L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N- [N-acetyl-O-benzyl-L-seryl] -S-benzyl-L-cysteinyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] - L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N-acetyl-O-benzyl-L-seryl] -D-tryp tophyl] -2-methyl-L-phenylalanyl] -3-methyl -L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N2- (N-acetyl-S, S-dioxo-L-methionyl] -N6-nitro-L-arginyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
2 (RS) - [[N- [N- [N- [N2- (N-acetyl-L-tyrosyl) -N6-nitro-L-arginyl] -2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde. 24. A compound of formula ID as defined in claim 5 selected from:
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -S, S-dioxo-L-methionyl] -D-valyl] -2-methyl-L-phenylalanyl ] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -S, S-dioxo-S-methyl-L-cysteinyl] -D-valyl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (RS) - [[N- [N- [N- [N- [N- (3-carboxypropionyl) -1- (2,4-dinotrophenyl) -Lh-istidyl] -D-valyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluoro butyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (N-(3-carboxypropionyl) -L-cysteinyl] - D-valyl] -2-methyl-L-phenylalanyl] -3-methyl- L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde and
1 (RS) - [[N- [N- [N- [N- [N-acetyl-1- (2,4-dinitrophenyl) -L-histidyl] -L-2-cyclohexylglycyl] -2-methyl-L -phenylala nyl] -3-methyl-L-valyl] -L-leucyl] -amino] propylboronic acid. 25. A compound of the formula IE, as specified in claim 6, selected from:
2 (RS) - [[N- [N- [N- [N- [N- [4- (4-methylphenyl) butyryl] -L-α-aspartyl] -L-α-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [3- (4-methylbenzoyl) propionyl] -L- α-aspartyl] -L-α-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- [2- (2- (2-methoxyethoxy) ethoxyacetyl] -L-α-aspartyl] -L-α-glutamyl] - 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluoro butyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- (4-oxo-2-thioxo-3-thiazolidinyl) acetyl] -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [3- (2-methyl-4-nitro-1-imidazolyl) propionyl] -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [5- hexinoyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(6-quinolyl) carbonyl] -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L -phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(6-oxo-3-pyranyl) carbonyl] -L-α-aspartyl] -L-α-glutamyl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- (1,3-Benzodioxol-5-yl) acetyl] - L-α-aspartyl] -L-α-glutamyl ] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (RS) - [[N- [N- [N- [N- [N - [(5,6-dihydro-6,6-dimethyl-4-oxo-4H-pyran-2-yl) carbonyl] - L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2- (2-naphthyl) acetyl] -L-α-aspartyl] -L-α-glutamyl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [N- (3-benzamidopropionyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinyl) carbonyl] -L-α- aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amine] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (3-methyl-2-thenoyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- (2-Cyclohexylacetyl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2 (RS) - (4-nitrophenyl) propionyl] - L-α-aspartyl] -L-α-glutamyl] -2 -methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
1 (RS) - [[N- [N- [N- [N- [N - [(6-oxo-6H-pyran-3-yl) carbonyl] -L-α-aspartyl] -L-α-glutamyl ] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid;
1 (RS) - [[N- [N- [N- [N- [N- (4-Acetamidobutyryl) -L-α-aspartyl] -L-α-glutamyl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] propylboronic acid and
1 (R3) - [[N- [N- [N- [N- [N- [N- (2-acetoxyacetyl) -L-α-aspartyl] -L- α-glutamyl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] - L-leucyl] amino] propylboronic acid. 26. A compound of formula IF as set out in claim 7 selected from:
2 (RS) - [[N- [N- [N- [N- [N- [2- (2,4,6-trimethylphenyl) acetyl] - L-seryl] -O-benzyl-D-seryl] - 2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (RS) - [[N- [N- [N- [N- [N - [(1H-benzotriazol-5-yl) carbonyl-L-seryl] -O-benzyl-D-seryl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (RS) - [[N- [N- [N- [N- [N- [4- (phenylcarbamoyl) butyryl] -L-seryl] -O-benzyl-D-seryl] -2-methyl-L- phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N- [2 - [(4,6-dimethyl-2-pyrimidinyl) thio] acetyl] -L-seryl] -O-benzyl -D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-tri fluorobutyraldehyde;
2 (RS) - [[N- [N- [N- [N- [N - [(2-chloro-3-pyridyl) carbonyl] -L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (RS) - [[N- [N- [N- [N- [N - [(9-hydroxy-9-fluorenyl) carbonyl-L-seryl] -O-benzyl-D-seryl] -2-methyl -L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (RS) - [[N- [N- [N- [N- [N - [(2-furoyl) -L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde;
2 (R3) - [[N- [N- [N- [N- [N- [2 (RS) - (4-nitrophenyl) propionyl] - L-seryl] -O-benzyl-D-seryl] -2 -methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (R3) - [[N- [N- [N- [N- [N- [2- (2-chlorophenyl) acetyl] -L-seryl] -O-benzyl-D-seryl] -2-methyl- L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd;
2 (R3) - [[N- [N- [N- [N- [N- (2-Ethoxyacetyl) -L-seryl] -O-benzyl-D-seryl] -2-methyl-L-phenylalanyl] - 3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyraldehyde and
2 (R3) - [[N- [N- [N- [N- [N - [(3-fluoro-4-hydroxyphenyl) acetyl] - L-seryl] -O-benzyl-D-seryl] -2- methyl-L-phenylalanyl] -3-methyl-L-valyl] -L-leucyl] amino] -4,4,4-trifluorobutyralde hyd. 27. A compound according to any one of claims 1 to 26 for use as a therapeutically active substance, in particular as antiviral and especially anti-He patitis C, hepatitis G and human GB viruses. 28. A method of making a compound according to any one of claims 1 to 26, the method comprising

• a) for the preparation of a compound of formula I, wherein E CHO means that an acetal of the general formula
  wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 have} the meanings given in claim 1 and are subject to the reservation indicated, deacetalized and, if necessary, the protective groups split off, with the proviso that all carboxy, hydroxy and / or aminocarbonyl groups that are present are in protected form, and R ¹⁰ and R ^{11 are} each lower alkyl groups, or
• b) for the preparation of a compound of formula I, wherein EB (OH) is ₂ , in a substituted dioxabo rolan of the general formula
  wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 have} the meanings given in claim 1 and are subject to the reservation specified therein, performs a ring opening, and, if necessary , Splitting off protective groups, with the proviso that all carboxy, hydroxy and / or aminocarbonyl groups present are in protected form, and Q is a group of the formula
  means in which R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ each represent hydrogen or lower alkyl radicals and R ¹⁶ and R ¹⁷ each represent hydrogen or lower alkyl radicals and
• c) if desired, converting an acidic compound of formula I that has been obtained into a salt with a base.

29. The method of claim 28, wherein the acetal of the formula II or the substituted dioxaborolane of the formula III, wherein Q represents a group of formula (a) Solid phase peptide synthetic resin is bound. 30. Acetals of formula II as indicated in claim 28. 31. Substituted dioxaborolanes of formula III, as in An pronounced 28. 32. drugs, especially antiviral drugs, especially medicines for hepatitis C, hepatitis G and human GB viruses containing a compound after one of claims 1 to 26 together with a pharmaceutical acceptable carrier.   33. Use of a compound according to one of claims 1 to 26 for the manufacture of an antiviral drug, especially a drug against hepatitis C, He patitis G and human GB viruses.